Methods

EARLY ACS was an international, multicenter, randomized trial conducted from May 2004 to August 2008 among 9,406 patients with high-risk NSTEACS for whom angiography was planned within 12 to 72 hours after randomization. The main results and details of the design are published elsewhere. The angiographic data were collected and analyzed by the pharmacologic/percutaneous endoluminal revascularization for unstable syndromes and its evaluation (PERFUSE) study group, an academic research organization. The statistical analyses of the angiographic substudy were performed by the TIMI study group and the Duke Clinical Research Institute. The EARLY ACS angiographic substudy manuscript was drafted by the director and members of the PERFUSE core laboratory. National and local regulatory and ethics committees approved the EARLY ACS trial. All patients provided written informed consent.

Details of entry criteria, randomization, and treatment assignment are as previously described elsewhere. Patients were randomly assigned to either early routine or delayed provisional eptifibatide in a 1:1 ratio. The early routine group was administered early eptifibatide in 2 boluses (180 μg/kg of body weight) 10 minutes apart, although the delayed provisional group was initially administered matching placebo boluses. An infusion of 2.0 μg/kg/min of eptifibatide or matching placebo was administered concurrently with the first bolus. A reduced infusion rate of 1.0 μg/kg/min was administered if creatinine clearance was <50 ml/min, and the infusion rate was reduced by 1/3 in cases of bleeding at the discretion of the Investigator.

The investigators were also able to request a PCI study-drug kit before PCI for patients who they deemed would benefit from eptifibatide based on clinical evidence and angiographic findings at the time of cardiac catheterization. The first bolus of the PCI study-drug kit contained placebo for those who had been randomized to early eptifibatide (i.e., the early routine group) and eptifibatide for patients who were administered early placebo (i.e., delayed provisional group). Concurrently, the blinded administration of the initial study drug (either eptifibatide or placebo) was stopped, and an open-label infusion of eptifibatide was begun and continued for 18 to 24 hours after PCI. If a provisional dose of a study drug was not administered before PCI, the initial infusion was continued without a change for 18 to 24 hours after PCI.

During PCI, if a thrombotic complication occurred after the guidewire passage across the lesion, investigators were permitted to request a kit that contained bolus therapy that was different from the initial study-group assignment (termed a bailout kit). The use of bailout kits for any one of the 7 predefined procedural complications was considered “thrombotic bailout,” and such cases were reviewed by the clinical events committee. TBO represents refractory ischemia that occurs during the course of PCI and is defined as the administration of eptifibatide after the initiation of PCI (defined as the time when the wire passes the lesion) for the management of any one of the following complications: decrement in TIMI flow grade, dissection with decreased flow, distal embolization, side branch closure, abrupt closure of the culprit vessel, clinical instability believed to be due to coronary ischemia and/or thrombotic complications, or prolonged ischemia (ischemic symptoms or ST-segment changes that develop during the procedure). For patients undergoing PCI, the duration of the infusion was ≤96 hours; longer infusions (up to 120 hours) were allowed to ensure a minimum 18-hour infusion after PCI.

If early clopidogrel was used, the recommended loading dose was 300 mg. A 600-mg loading dose was permitted during PCI if no previous loading dose had been administered. The recommended maintenance dose of clopidogrel was 75 mg daily. Other medical therapies were administered according to the standard practice and guidelines. All 440 study centers in 29 countries were invited to participate in the angiographic substudy. Of these, 178 centers in 23 countries participated in the angiographic substudy. Submission of the angiographic images to the core lab was at the discretion of the investigator. Angiography was performed according to the local practice patterns.

Detailed analysis was carried out at the PERFUSE angiographic core laboratory on all angiographic images in the substudy to determine the angiographic primary end point (TMPG 3 before and after PCI) and other angiographic parameters including quantitative coronary angiography, corrected TIMI frame count, TIMI flow grade, TIMI thrombus grade (see online appendix for definitions), and angiographic complications including angiographic TBO events such as distal embolization, side branch closure, no reflow, and abrupt closure of the culprit vessel. All investigators at the PERFUSE angiographic core laboratory were blinded to treatment assignment. The efficacy and safety end points for the main study are described in detail elsewhere. Briefly, the primary efficacy composite end point was death from any cause, MI, RIUR, or TBO at 96 hours. The key secondary efficacy end point was a composite of death from any cause or MI within the first 30 days. Safety end points included rates of hemorrhage, transfusion, surgical re-exploration, stroke, thrombocytopenia, and serious adverse events at 120 hours after randomization.

Baseline characteristics, angiographic findings, and clinical outcomes (death, MI, stroke, bleeding, RIUR, and TBO) were summarized using means with SDs for continuous variables and frequencies for categorical variables. The Wilcoxon rank-sum test was used for comparisons of continuous variables, and chi-square or Fisher’s exact test was used for comparisons of categorical variables. p Values (two-tailed) <0.05 were considered statistically significant. All analyses were performed using Stata/IC, version 10.1 (StataCorp, College Station, Texas).

Results

The angiographic substudy consisted of 2,066 patients (n = 1,042 in the early routine eptifibatide group, n = 1,024 in the delayed provisional eptifibatide group) from the 9,406 EARLY ACS efficacy cohort. The study flow is shown in Figure 1 . In total, 428 of 2,066 patients (21%) in the angiographic substudy received a PCI study-drug kit, and 257 of 2,066 patients (12%) received a bailout kit in this angiographic substudy.

Study flow chart—EARLY ACS angiographic substudy.

Baseline characteristics of patients included in the angiographic substudy are listed in Tables 1 and 2 . Table 1 compares patients who were in the main study versus those who were and were not included in the angiographic substudy. There were fewer women, fewer patients recruited from Europe, and fewer patients with previous congestive heart failure in the angiographic substudy compared with the main trial. There were more patients with previous PCI and previous coronary artery bypass graft (CABG) who were represented in the angiographic substudy.

There were no significant differences in the baseline characteristics or medical therapies during the index hospitalization between the patients randomized to early routine versus delayed provisional eptifibatide in the angiographic substudy ( Table 2 ). Overall, 72% underwent PCI in each group (p = 0.92), and there were no differences in the time from randomization to PCI, duration of study-drug infusion before (mean 31 hours) or after PCI (mean 20 hours) between treatment groups ( Table 3 ).

There was no difference in the pre-PCI TMPG 3 between early routine and delayed provisional groups (409 [43.7%] vs 420 [44.9%], respectively, p = 0.58; Figure 2 ; Table 4 ). In the early eptifibatide group, TMPG 3 was identified in 49.2%, 47.6%, and 33.0% patients who received neither PCI active nor PCI bailout kit (n = 415), the active kit (n = 209), and bailout kit (n = 124), respectively. In the delayed provisional eptifibatide group, TMPG 3 was identified in 49.2%, 45.8%, and 43.6% of patients who received neither PCI active nor PCI bailout kit (n = 383), active kit (n = 219), and bailout kit (n = 286), respectively.

Angiographic and clinical end points in the EARLY ACS angiographic substudy.

There was also no difference in the post-PCI TMPG 3 between early routine versus delayed provisional group (311 [52.4%] vs 279 [50.1%], p = 0.73; Figure 2 ; Table 5 ). In the early eptifibatide group, TMPG 3 was identified in 56.5%, 52.1%, and 42.0% of patients who received neither active nor bailout kit, active kit, and bailout kit, respectively. The corresponding rates in the delayed provisional eptifibatide group were 51.1%, 52.1%, and 42.3%, respectively.

Table 5

Post-PCI angiographic characteristics of patients in the angiographic substudy

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Usefulness of the SYNTAX Score to Predict Acute Kidney Injury After Percutaneous Coronary Intervention (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial)
2. Impact of High-Dose Atorvastatin Therapy and Clinical Risk Factors on Incident Aortic Valve Stenosis in Patients With Cardiovascular Disease (from TNT, IDEAL, and SPARCL)
3. Left Ventricular Systolic Function Following Alcohol Septal Ablation for Symptomatic Hypertrophic Cardiomyopathy
4. Cardiotoxicity Research in Breast Cancer Patients: Past and Future

Stay updated, free articles. Join our Telegram channel

Join