Efficacy and safety of bevifibatide in patients with acute coronary syndrome undergoing percutaneous coronary intervention (BES-PCI): A multicenter, randomized, double-blinded, placebo-controlled, phase III trial

Glycoprotein (GP) IIb/IIIa receptor inhibitors have been demonstrated to protect against ischemic complications of percutaneous coronary intervention (PCI) and improve the clinical outcomes of acute coronary syndrome (ACS). Recent guidelines recommend the use of a GP IIb/IIIa inhibitor when there is evidence of no-reflow or a thrombotic complication during PCI, or in the setting of high-risk PCI in patients who have not been pretreated with P2Y12 receptor inhibitors.[1] As a member of a new class of GP IIb/IIIa receptor antagonists, bevifibatide is a cyclic heptapeptide intravenous formulation containing six amino acids and a mercapto propionyl (des-amino cysteinyl) residue. In addition to blocking fibrinogen binding to GP IIb/IIIa (integrin αIIbβ3), bevifibatide can also block the binding of circulating vitronectin to integrin αvβ3, which is structurally similar to GP IIb/IIIa. Bevifibatide can not only prevent platelet aggregation-induced thrombus formation but also prevent integrin αvβ3-induced restenosis. However, the use of bevifibatide still lacks large-scale randomized clinical trials powered to explore clinical endpoints. The randomized controlled trial of Bevifibatide in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (BES-PCI trial) was designed to evaluate the efficacy and safety of bevifibatide in patients with ACS undergoing PCI. Bevifibatide was registered at the Chinese Clinical Trial Registry (No. ChiCTR2400092377) and www.chinadrugtrials.org.cn (No. CTR20130809). Trial design and ethical approval: This trial is a multicenter, randomized, double-blinded, parallel placebo-controlled, phase III study. This study complied with the Declaration of Helsinki in terms of investigations in humans, and its protocol was submitted and approved by the institutional ethics committee at each participating clinical site before the initiation of the investigation [Supplementary File 1, https://links.lww.com/CM9/C667]. All patients provided written informed consent before enrollment. Participants: Patients who were 18–75 years old, diagnosed with ACS, and needed PCI were enrolled in this study. The exclusion criteria are described in detail in the Expanded Methods in the Supplementary File 2, https://links.lww.com/CM9/C668. Interventions: Patients were randomly assigned in a 1:1 ratio to receive either bevifibatide or placebo. All the patients were pretreated with aspirin and clopidogrel (with the use of a loading dose of 300 mg aspirin and 300–600 mg clopidogrel) on the day of randomization. Immediately before PCI, patients were randomly allocated to receive bevifibatide, given as a 220 μg/kg bolus and a continuous infusion of 2.5 μg·kg−1·min−1 for 24 hours, or placebo. PCI was performed according to standard techniques. The technical aspects of the procedure, including the use of anticoagulation drugs and the type of stent, were left to the operator’s discretion. After the procedure, all patients were strongly recommended to receive optimal pharmacological therapy at the discretion of the responsible clinicians to control their various health conditions. Bailout GP IIb/IIIa inhibitor therapy: In the case of the emergent situations requiring open-label GP IIb/IIIa inhibitor therapy (for the direct treatment of abrupt closure, no reflow, coronary thrombosis, or other similar PCI complications), the study drug infusion was discontinued and switched to an infusion of open-label bevifibatide. Bailout GP IIb/IIIa inhibitor use did not result in unblinding of study drug assignment. Outcomes: The primary efficacy endpoints were the composite of death, myocardial infarction, urgent target vessel revascularization, and thrombotic situations requiring bailout GP IIb/IIIa inhibitor therapy within 30 days after PCI. The secondary endpoints were the composite of death, myocardial infarction, urgent target vessel revascularization, and thrombotic situations requiring bailout GP IIb/IIIa inhibitor therapy within 48 hours and 7 days after PCI. Safety endpoints included thrombolysis in myocardial infarction (TIMI) major bleeding, blood transfusions, and stroke through 48 hours or hospital discharge, whichever occurred first. Definitions of the endpoints are provided in the Expanded Methods in the Supplementary File 2, https://links.lww.com/CM9/C668. All the primary and secondary endpoints were adjudicated by an independent clinical event committee. Clinical and laboratory findings of the patients were assessed at baseline. Patients were scheduled for follow-up visits at 48 hours, 1 week, and 1 month after the index PCI. Patient data, including clinical status, all interventions, outcome events, and adverse events, were recorded at follow-up. Sample size: The sample size for this study was determined using Cox’s proportional hazards model, which was designed to compare two survival curves. Based on previous data involving a similar patient population profile, primary endpoint rates of 6.8% and 10.5% were assumed for the bevifibatide and control groups, respectively. Therefore, with 80% power and a 2-sided type I error of 5%, a sample size of 743 patients in each group would be able to demonstrate the difference between the two groups for the primary endpoint. Assuming up to 15% loss to follow-up, a total of 1750 patients were deemed necessary. Statistical analysis: Categorical data on demographic, medication, and procedural characteristics are presented as numbers (percentages). Continuous variables are expressed as the mean ± standard deviation (SD). Kaplan–Meier curves for time-to-event analysis were plotted based on the time of randomization to the occurrence of the first event during follow-up. Confidence intervals (CIs) are the Wald CIs. Hazard ratios (HRs) with 95% CIs were estimated by Cox regression analysis after adjusting for center effects. All the primary and secondary endpoints were analyzed on intention-to-treat and per-protocol sets. A Cox proportional hazards model was used for analysis of post hoc subgroups, defined according to the classification of ACS, creatinine clearance, smoking status, diabetes, history of stroke, hypertension, age, and sex. Those with missing primary and secondary endpoints were censored at the time of withdrawal of consent or loss to follow-up. All the analyses in this study were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). Baseline characteristics: Between December 31, 2012, and April 13, 2016, 1750 subjects from 45 Chinese cardiovascular centers were screened. Among them, 295 patients from 7 centers (147 patients in the bevifibatide group and 148 patients in the placebo group) were excluded due to audit failure or poor quality control. In addition, 1 did not meet the eligibility criteria, 8 declined to participate, and 4 lacked efficacy evaluation. Ultimately, 1442 patients were randomly assigned to the bevifibatide (N = 721) and placebo (N = 721) groups. The baseline demographic, clinical, and interventional characteristics of the two groups are described in Supplementary Table 1, https://links.lww.com/CM9/C669. The mean age was 58.4 years, and 1078 of the patients (74.8%) were men. A total of 484 patients (33.6%) had previous coronary artery disease, 104 (7.2%) had previous PCI, and 74 (5.1%) had previous stroke. Sex, age, body mass index, comorbidity, and other medical histories were similar between the two groups. In the bevifibatide group, 423 subjects (58.7%) were diagnosed with unstable angina (UA), 130 (18.0%) with non-ST-elevation myocardial infarction (NSTEMI), and 170 (23.6%) with ST-elevation myocardial infarction (STEMI). In the control group, 413 (57.3%), 123 (17.1%), and 188 (26.1%) patients were diagnosed with UA, NSTEMI, and STEMI, respectively. No significant difference was detected in the classification of ACS between the two groups (P >0.05). Most of the patients enrolled underwent stent implantation, with the number and type of stents being similar between the two groups. A total of 132 patients in the bevifibatide group and 132 in the placebo group were assessed as being noncompliant with the protocol due to the use of drugs forbidden in the protocol, an inadequate interval between the use of low-molecular-weight heparin and PCI, or infusion of the study drug in a manner that did not comply with the protocol. Supplementary Figure 1, https://links.lww.com/CM9/C669 shows the flow of patients through the trial. Efficacy of bevifibatide: The primary efficacy endpoint occurred in 25/721 (3.47%) patients in the bevifibatide group and 42/721 (5.83%) patients in the placebo group (HR 0.57, 95% CI 0.35–0.94, P = 0.026), with the main decrease in thrombotic situations requiring bailout GP IIb/IIIa inhibitor therapy (1.94% vs. 4.30%, HR 0.44, 95% CI 0.23–0.82, P = 0.009) [Supplementary Table 2, https://links.lww.com/CM9/C669]. Kaplan–Meier curves revealed a significant reduction in the risk for the primary endpoint in the bevifibatide group (P = 0.026) [Figure 1]. The incidence rates of the individual components of the primary efficacy endpoints (death, myocardial infarction, and urgent target vessel revascularization) were similar between the two groups. There was consistency in the reduction in composite efficacy endpoints at 48 hours (HR 0.50, 95% CI 0.29–0.86, P = 0.013) and 7 days (HR 0.54, 95% CI 0.31–0.93, P = 0.025). More than 75% of all events occurred during the first 48 hours. Per-protocol analyses yielded similar results for the primary endpoint (HR 0.54, 95% CI 0.31–0.93, P = 0.025) and the secondary endpoints [Supplementary Table 3, https://links.lww.com/CM9/C669].Figure 1: Kaplan–Meier curves revealed a significant reduction in the risk for the efficacy endpoint in the bevifibatide group. PCI: percutaneous coronary intervention.Safety of bevifibatide: Bleeding events were more common among patients receiving bevifibatide (bevifibatide vs. placebo: 7.88% vs. 4.57%, P = 0.012), most of which were TIMI minimal to minor bleeding, including gingival and gastrointestinal bleeding as well as bleeding at the puncture site. Notably, compared with placebo, bevifibatide did not increase TIMI major bleeding (bevifibatide vs. placebo: 0.28% vs. 0, P = 0.762) [Supplementary Table 4, https://links.lww.com/CM9/C669]. Two major bleeding events in the bevifibatide group included 1 intracranial hemorrhage and 1 case of gastrointestinal bleeding. Neither blood transfusions nor stroke were observed in this study [Supplementary Table 2, https://links.lww.com/CM9/C669]. No patient withdrew from the study due to the bleeding events. Subgroup analysis: In the post hoc subgroup analysis, the beneficial effect of bevifibatide compared with that of placebo was generally consistent across all the subgroups with no significant interaction. Notably, patients who were diagnosed with NSTEMI and aged over 65 years gained greater benefits from bevifibatide [Supplementary Figure 2, https://links.lww.com/CM9/C669]. Adverse events: Serious adverse events occurred in 55 patients (7.61%) in the bevifibatide group and 63 patients (8.73%) in the placebo group. There was no significant between-group difference in the incidence of serious adverse events between the groups. The incidence of most conditions of interest was similar between the two groups, except for hepatic disorders. Notably, the incidence of thrombocytopenia was similar between the two groups (bevifibatide vs. placebo: 0.55% vs. 0.28%, risk ratio 1.96, 95% CI 0.36–10.66, P = 0.687). Severe thrombocytopenia (<50 × 109/L) was not found in this trial [Supplementary Table 5, https://links.lww.com/CM9/C669]. Currently available GP IIb/IIIa receptor antagonists include abciximab, eptifibatide, and tirofiban.[2] They are not recommended as part of routine upstream therapy in patients with ACS but are good options for reducing thrombus burden in bail-out situations and are usually used as bridging strategies in clinical practice.[3] The addition of a GP IIb/IIIa inhibitor may decrease the occurrence of periprocedural infarction in unrecognized high-risk patients undergoing PCI.[4] The BES-PCI trial revealed that in Chinese patients diagnosed with ACS undergoing PCI, compared with placebo, GP IIb/IIIa receptor blockade with bevifibatide significantly reduced the primary efficacy endpoint. The occurrence of the efficacy endpoint was consistently significantly lower in the bevifibatide group at 48 hours and 7 days. This decrease was mainly driven by a reduction in the thrombotic situation requiring bailout GP IIb/IIIa inhibitor therapy without an increase in major bleeding events. Patients who were diagnosed with NSTEMI and aged over 65 years seemed to benefit more from bevifibatide. Notably, severe thrombocytopenia was not found in this trial. Conflicts of interest The Bevifibatide in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (BES-PCI) trial was sponsored by Bio-thera Solutions, Ltd., Guangzhou, Guangdong, China.