Prepercutaneous coronary intervention Zalunfiban dose-response relationship to target vessel blood flow at initial angiogram in st-elevation myocardial infarction - A post hoc analysis of the cel-02 phase IIa study.

BACKGROUND: Zalunfiban (RUC-4) is a novel, subcutaneously administered glycoprotein IIb/IIIa inhibitor (GPI) designed for prehospital treatment to initiate reperfusion in the infarct-related artery (IRA) before primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction (STEMI). Since GPIs have been reported to rapidly reperfuse IRAs, we assessed whether there was a dose-dependent relationship between zalunfiban treatment and angiographic reperfusion indices and thrombus grade of the IRA at initial angiogram in patients with STEMI. METHODS: This was a post hoc analysis from the open-label Phase IIa study that investigated the pharmacodynamics, pharmacokinetics, and tolerability of three doses of zalunfiban - 0.075, 0.090 and 0.110 mg/kg - in STEMI patients. This analysis explored dose-dependent associations between zalunfiban and three angiographic indices of the IRA, namely coronary and myocardial blood flow and thrombus burden. Zalunfiban was administered in the cardiac catheterization laboratory prior to vascular access, ∼10 to 15 minutes before the initial angiogram. All angiographic data were analyzed by a blinded, independent, core laboratory. RESULTS: Twentyfour out of 27 STEMI patients were evaluable for angiographic analysis (0.075 mg/kg [n=7], 0.090 mg/kg [n=9], and 0.110 mg/kg [n=8]). TIMI flow grade 2 or 3 was seen in 1/7 patients receiving zalunfiban at 0.075 mg/kg, in 6/9 patients receiving 0.090 mg/kg, and in 7/8 patients receiving 0.110 mg/kg (ptrend = 0.004). A similar trend was observed based on TIMI flow grade 3. Myocardial perfusion was also related to zalunfiban dose (ptrend = 0.005) as reflected by more frequent TIMI myocardial perfusion grade 3. Consistent with the dose-dependent trends in greater coronary and myocardial perfusion, TIMI thrombus ≥4 grade was inversely related to zalunfiban dose (ptrend = 0.02). CONCLUSION: This post hoc analysis found that higher doses of zalunfiban administered in the cardiac catheterization lab prior to vascular access were associated with greater coronary and myocardial perfusion, and lower thrombus burden at initial angiogram in patients with STEMI undergoing primary percutaneous coronary intervention.

Prehospital treatment with zalunfiban (RUC-4) in patients with ST- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial.

BACKGROUND: Early and complete restoration of target vessel patency in ST-elevation myocardial infarction (STEMI) is associated with improved outcomes. Oral P2Y12 inhibitors have failed to demonstrate either improved patency or reduced mortality when administered in the prehospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the prehospital setting. Zalunfiban, a novel subcutaneously administered glycoprotein IIb/IIIa inhibitor designed for prehospital administration, has shown to achieve rapid, high-grade platelet inhibition that exceeds that of P2Y12 inhibitors. Whether prehospital administration of zalunfiban can improve clinical outcome is unknown. HYPOTHESIS: The present study is designed to assess the hypothesis that a single, prehospital injection of zalunfiban given in the ambulance, in addition to standard-of-care in patients with STEMI with intent to undergo primary percutaneous coronary intervention (PCI) will improve clinical outcome compared to standard-of-care with placebo. STUDY DESIGN: The ongoing CELEBRATE trial (NCT04825743) is a phase 3, randomized, double-blinded, placebo-controlled, international trial. Patients with STEMI intended to undergo primary PCI will receive treatment with a single subcutaneous injection containing either zalunfiban dose 1 (0.110 mg/kg), zalunfiban dose 2 (0.130 mg/kg) or placebo, and the study drug will be administered in the ambulance before transportation to the hospital. A target of 2499 patients will be randomly assigned to one of the treatment groups in a 1:1:1 ratio, ie, to have approximately 833 evaluable patients per group. The primary efficacy outcome is a ranked 7-point scale on clinical outcomes. The primary safety outcome is severe or life-threatening bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria. SUMMARY: The CELEBRATE trial will assess whether a single prehospital subcutaneous injection of zalunfiban in addition to standard-of-care in patients with STEMI with intent to undergo primary PCI will result in improved clinical outcome.

Current and Future Insights for Optimizing Antithrombotic Therapy to Reduce the Burden of Cardiovascular Ischemic Events in Patients with Acute Coronary Syndrome.

The pharmacological treatment strategies for acute coronary syndrome (ACS) in recent years are constantly evolving to develop more potent antithrombotic agents, as reflected by the introduction of more novel P2Y12 receptor inhibitors and anticoagulants to reduce the ischemic risk among ACS patients. Despite the substantial improvements in the current antithrombotic regimen, a noticeable number of ACS patients continue to experience ischemic events. Providing effective ischemic risk reduction while balancing bleeding risk remains a clinical challenge. This updated review discusses the currently approved and widely used antithrombotic agents and explores newer antithrombotic treatment strategies under development for the initial phase of ACS.

Complementary Pharmacotherapy for STEMI Undergoing Primary PCI: An Evidence-Based Clinical Approach.

Antithrombotic therapy is the cornerstone of pharmacological treatment in patients undergoing primary percutaneous coronary intervention (PCI). However, the acute management of ST elevation myocardial infarction (STEMI) patients includes therapy for pain relief and potential additional strategies for cardioprotection. The safety and efficacy of some commonly used treatments have been questioned by recent evidence. Indeed a concern about morphine use is the interaction between opioids and oral P2Y12 inhibitors; early beta-blocker treatment has shown conflicting results for the improvement of clinical outcomes; and supplemental oxygen therapy lacks benefit in patients without hypoxia and may be of potential harm. Other additional strategies remain disappointing; however, some treatments may be selectively used. Therefore, we intend to present a critical updated review of complementary pharmacotherapy for a modern treatment approach for STEMI patients undergoing primary PCI.