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.

Prehospital triage in the ambulance reduces infarct size and improves clinical outcome.

BACKGROUND: We evaluated the effect of prehospital triage (PHT) in the ambulance on infarct size and clinical outcome and studied its relationship to the distance of patient's residence to the nearest percutaneous coronary intervention (PCI) center. METHODS: All consecutive ST-segment elevation myocardial infarction patients who were transported to the Isala klinieken from 1998 to 2008 were registered in a dedicated database. Of these, 2,288 (45%) were referred via a spoke center and 2.840 (55%) via PHT. RESULTS: PHT patients were more often treated within 3 hours after symptom onset (46.2% vs 26.8%, P < .001), more often had a post-procedural thrombolysis in myocardial infarction (TIMI) 3 flow (93.0% vs 89.7%, P < .001) had a smaller infarct size (peak creatine kinase 2,188 ± 2,187 vs 2,575 ± 2,259 IU/L, P < .001) and had a lower 1-year mortality (4.9% vs 7.0%, P = .002). After multivariate analysis, PHT was independently associated with ischemic time less than 3 hours (OR 2.45, 95% CI 2.13-2.83), a peak creatine kinase less than the median value (OR 1.19, 95% CI 1.04-1.36) and a lower 1-year mortality (OR 0.67, 95% CI 0.50-0.91). The observed differences between PHT patients and the spoke group were more pronounced in the subgroup of patients living >38 km from the PCI center. CONCLUSION: PHT in the ambulance is associated with a shorter time to treatment, a smaller infarct size and a more favorable clinical outcome, especially with longer distance from the patient's residence to the nearest PCI center. Therefore, PHT in the ambulance may reduce the negative effect of living at a longer distance from the PCI center.

Feasibility and benefit of prehospital diagnosis, triage, and therapy by paramedics only in patients who are candidates for primary angioplasty for acute myocardial infarction.

BACKGROUND: Despite data showing that time to treatment is very important in ST-elevation myocardial infarct patients, unacceptable long delays to reperfusion remain present in daily life practice. We sought to evaluate the feasibility and effect of improving logistics by early infarct diagnosis in the ambulance and immediate triage to a percutaneous coronary intervention (PCI) center performed by paramedics only without interference of a physician. METHODS: In the On-TIME study, 209 patients were included after prehospital infarct diagnosis and triage in the ambulance (ambulance group, n = 209). Infarct diagnosis was made by highly trained paramedics with the help of a computerized electrocardiographic algorithm. The accuracy of diagnosis, time to treatment, left ventricular function, and clinical outcome were compared with the patients who were diagnosed and triaged at a referral non-PCI center (referred group, n = 258). Left ventricular function was assessed before discharge using a nuclear technique. RESULTS: Acute myocardial infarction was accurately diagnosed in 95% of patients in the ambulance group, as compared with 99% in the referred group (P = .01). The percentage of patients in whom pharmacologic pretreatment (heparin, aspirin, tirofiban, or placebo) was initiated in the ambulance within 90 minutes after the onset of symptoms was 59% in the ambulance group versus 43% in the referred group (P < .01). A left ventricular ejection fraction of <40% was present in 25% in the ambulance group, as compared with 38% in the referred group (P = .013). After multivariate analysis, ambulance triage was independently associated with a left ventricular ejection fraction >40% and a favorable long-term clinical outcome. CONCLUSIONS: Early, prehospital infarct diagnosis, triage, and therapy in the ambulance with direct transportation to the nearest PCI center, performed by trained paramedics only, is feasible in 95% of patients. Ambulance triage resulted in earlier diagnosis and initiation of therapy and was independently associated with a better left ventricular function and clinical outcome, as compared with triage and transportation from a referral non-PCI center.

How to set up an effective national primary angioplasty network: lessons learned from five European countries.

AIMS: Percutaneous coronary interventions (PCI) are used to treat acute and chronic forms of coronary artery disease. While in chronic forms the main goal of PCI is to improve the quality of life, in acute coronary syndromes (ACS) timely PCI is a life-saving procedure - especially in the setting of ST-elevation myocardial infarction (STEMI). The aim of this study was to describe the experience of countries with successful nationwide implementation of PCI in STEMI, and to provide general recommendations for other countries. METHODS AND RESULTS: The European Association of Percutaneous Cardiovascular Interventions (EAPCI) recenty launched the Stent For Life Initiative (SFLI). The initial phase of this pan-European project was focused on the positive experience of five countries to provide the best practice examples. The Netherlands, the Czech Republic, Sweden, Denmark and Austria were visited and the logistics of ACS treatment was studied. Public campaigns improved patient access to acute PCI. Regional networks involving emergency medical services (EMS), non-PCI hospitals and PCI centres are useful in providing access to acute PCI for most patients. Direct transfer from the first medical contact site to the cathlab is essential to minimise the time delays. Cathlab staff work is organised to provide acute PCI services 24 hours a day / seven days a week (24/7). Even in those regions where thrombolysis is still used due to long transfer distances to PCI, patients should still be transferred to a PCI centre (after thrombolysis). The highest risk non-ST elevation acute myocardial infarction patients should undergo emergency coronary angiography within two hours of hospital admission, i.e. similar to STEMI patients. CONCLUSIONS: Three realistic goals for other countries were defined based on these experiences: 1) primary PCI should be used for >70% of all STEMI patients, 2) primary PCI rates should reach >600 per million inhabitants per year and 3) existing PCI centres should treat all their STEMI patients by primary PCI, i.e. should offer a 24/7 service.