Trial Design And Study Participants
We conduct this single-center randomized, single-blinded parallel pilot trial to compare a prolonged stent deployment strategy with a rapid inflation/deflation deployment strategy. The randomization was performed using a simple random sampling method that was generated by a computer program. The random allocation list was enclosed in sequentially numbered, opaque, sealed envelopes. The eligible patients were assigned in a 1:1 ratio to the prolonged inflation group or the rapid inflation/deflation group. The trial design was approved by the Regional Ethics Review Board of West China Hospital. The research paper is written in accordance with the international CONSORT 2010 statement[12].
Patients were eligible for enrollment if they met the following criteria: 1) age ≥ 18 years; 2) patients with STEMI who were referred to PPCI within 12 hours after the onset of symptoms and with ST-segment elevation ≥ 1 mm in ≥ 2 contiguous leads or a presumed new left bundle branch block or a true posterior myocardial infarction; 3) admission within 12 hours of symptom onset or admission between 12 and 24 hours if there was evidence of continuing ischemia. The exclusion criteria were: the left main coronary artery was a target vessel; an artery reference diameter༜2 mm; vessel calcification or tortuosity, a true bifurcation lesion; cardiogenic shock; prior coronary artery surgery; previous percutaneous coronary intervention(PCI) of the target segment; a contraindication to CMR imaging (e.g., pacemaker, claustrophobia),and inability to give informed consent.
Procedures
Patients who fulfilled the inclusion criteria were randomly assigned after coronary angiography to the prolonged stent deployment group or to the conventional rapid inflation/deflation deployment group during PCI. An experienced cardiologists preformed the procedures. All patients received 300 mg of oral aspirin and 600 mg clopidogrel (or 180 mg ticagrelor) as soon as the diagnosis was confirmed. Heparin (60U/kg) was given to all patients in the emergency department and was administered throughout the procedure to maintain an ACT༞300 seconds. Patients were immediately taken to the cardiac catheterization lab, and coronary angiography was performed by using the standard Judkins technique with a transradial approach. If the patient had a high thrombus burden, thrombus aspiration was performed when the floppy, steerable guidewire passed through the target lesion, according to the operator’s judgment. If the operator predicted that direct stenting was possible, predilation was not performed. if direct stenting was impossible, predilation with a single low-pressure inflation was performed. In all patients, only the infarct-related artery was treated.
All placed stents were drug-eluting stents, and patients were given the option between two commercially available drug-eluting stents: the PROMUS Element stent (Boston Scientific, Boston, Massachusetts) or a GuReater stent (Lepu, China). The diameters of the stent and balloon were selected by visual estimation to achieve a balloon-to-vessel ratio of 1:1. In the experimental group, the stent was deployed with a single balloon inflation, and low-pressure inflation was sustained for > 30 seconds after the target balloon inflation pressure had been achieved. If the patient could not tolerate the procedure, showed signs of ischemia, or had chest pain, arrhythmia, or a decrease in blood pressure, the stent balloon was immediately deflated. A rapid inflation/deflation strategy was adopted in the control group, in which the stent balloon inflation time was less than 10 seconds. Additional dilation, expansion pressure, and postdilation were left to the discretion of operators. For both study groups, a GP Ⅱb/Ⅲa inhibitor (tirofiban) was used as a preventive or bailout therapy at the operator’s discretion. After stent implantation, if the no-reflow phenomenon was present, pharmacological intervention including common vasodilators (nitroprusside, diltiazem) was used.
Endpoints, Assessment Of Outcomes And Definitions
The primary outcome of this study was the incidence of the no-reflow phenomenon according to TIMI flow. The no-reflow phenomenon was defined as a TIMI flow grade ≤ 2 that was transient or sustained after the occluded epicardial artery was opened; incomplete lesion dilation, epicardial vascular spasm, dissection or in situ thrombosis were carefully excluded[13]. Two experienced cardiologists independently assessed the occurrence of no-reflow after stent implantation, the TIMI flow grade, the TIMI frame count, and the myocardial blush grade on the most recent angiogram. Thrombolysis in the myocardial infarction (TIMI) risk score flow grading system was used to evaluate blood flow. TIMI 0 flow is defined as no antegrade flow beyond the point of occlusion. TIMI 1 flow is defined as faint antegrade flow beyond the occlusion with incomplete filling of the distal vascular bed. TIMI 2 flow is defined as delayed antegrade flow with complete filling of the distal vascular bed. TIMI 3 flow is defined as normal flow with complete filling of the distal vascular bed. The number of angiogram frames required for the dye to reach a specified distal segment in the coronary artery was referred to as the corrected TIMI frame count[14]. All angiograms were recorded on 21 mm cine film at 15 frames/second (UNIQ FD 10, Philips, USA). The myocardial blush grade (MBG) was used to assess the filling and clearance of contracts in the myocardium. MBG 0 was defined as no apparent tissue-level perfusion in the distribution of the culprit artery. MBG 1 was defined as no clearance from the microvasculature. MBG 2 was defined as the blush clearing slowly. MBG 2 was defined as blush beginning to clear during washout[15]. The thrombus burden was evaluated by the TIMI thrombus scale, which was classified as a grade between 0 and 5[16]. A heavy thrombus burden was considered to be present with a TIMI grade ≥ 4. Electrocardiographic resolution of ST-segment elevation was defined as an ST-segment reduction of > 50% in the same lead within 60 min after the index procedure[17].
The secondary outcomes were major adverse cardiovascular events (MACEs), which were defined as any events of target vessel revascularization, recurrent MI or cardiovascular mortality. These outcomes were examined 30 days and one year after the primary PCI. The procedure time, total fluoroscopy time, and radiation dose were also assessed. The safety outcome of major bleeding is defined using a definition of major bleeding from the International Society on Thrombosis & Hemostasis (ISTH)[18]; the bleeding events that are not defined as major will be counted as minor bleeding.
A subset of patients was included in the cardiac magnetic resonance (CMR) examination approximately 3 to 5 days after the index procedure. To assess infarct size, myocardial salvage index, presence and extent of MVO, myocardium hemorrhage, myocardial edema, and left ventricular ejection fraction(LVEF) and left ventricular(LV) volume. Examinations were performed on a 3.0-T whole-body scanner with an18-element body phased arraycoil (Skyra; Siemens Medical Solutions, Erlangen, Germany). Standard two-, three, and four-chamber cine images were acquired using a TrueFISP sequence. The area at risk was assessed on the initial examination using a T2-weighted short-tau inversion-recovery sequence. Infarct size, LVEF, and LV volume were assessed on both examinations using delayed, contrast-enhanced, electrocardiogram-triggered inversion-recovery images and steady-state free precession(SSFP) cine images. The myocardial salvage index was calculated as [area at risk (mass) – infarct size (mass)]/area at risk (mass). Delayed contrast-enhanced images were obtained 10 min after an intravenous injection of 0.1 mmol/kg body weight gadolinium-based contrast (Gadovist, Bayer Schering, Berlin, Germany). All images were obtained in the short-axis plane, with 8-mm slices without gaps covering the entire LV[19–21].
A subgroup analysis was prespecified to examine factors associated with an increased risk of the no-reflow phenomenon: age (≥ 65 and < 65 years), thrombus burden, thrombosis aspiration, direct stenting, infarct location (anterior and nonanterior), multiple complex lesions, and door-to-balloon time.
Statistical analysis
The trial was powered for the outcome of ST-segment reduction of > 50% in the same lead within 60 min after the index procedure. The results of previous studies showed that the incidence of electrocardiographic resolution was 60–70% under conventional rapid inflation/deflation strategy in PPCI. We therefore hypothesized that in our trial more patients in the prolonged inflation group achieved ST-segment reduction of > 50%, and the anticipated relative risk reduction (RRR) was 30%. We calculated that 53 patients would need to be enrolled in this study. The sample size was increased by about 10% to total 60 patients to account for loss to follow up. The data are expressed as percentages and means (standard deviations). Categorical variables were compared using the chi-square test at a two-sided significance level of 5%. Continuous variables were compared using t test or analysis of variance (ANOVA). A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 17.0 software (SPSS, Inc., Chicago, Illinois).