Prolonged Clinical Follow-up of OPTIMA-5

Study Overview
=================
Brief Summary
-----------------
The OPTIMA-5 trial is a prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose recombinant staphylokinase (r-SAK) with normal saline (NS) in patients with ST-segment elevation myocardial infarction (STEMI) presenting ≤12 hours of symptom onset and expected to undergo primary percutaneous coronary intervention (PPCI) within 120 minutes. The results of OPTIMA-5 showed that a single bolus r-SAK prior to PPCI for STEMI improves infarct related artery (IRA) patency and reduces infarct size without increasing major bleeding. On this basis, this study was designed to investigate the effect of the novel reperfusion strategy on 1-year outcomes of patients with STEMI.

Detailed Description
-----------------
Acute myocardial infarction (AMI) is one of the leading causes of death all over the world, and accounted for more than 100 thousand deaths in the US in 2019. Early PPCI reduces mortality in patients with STEMI. If PPCI cannot be performed within 120 minutes of presentation, guidelines recommend the use of thrombolytic therapy. However, it remains uncertain whether adjunctive thrombolytic therapy administered immediately prior to PPCI improves outcomes in patients undergoing the procedure within 120 minutes. SAK is a fibrin specific fibrinolytic agent produced by Staphylococcus aureus that was first discovered in 1948. A recombinant form of SAK was approved by China Food and Drug Administration (CFDA) for treatment of patients with STEMI. It has been demonstrated that r-SAK is more potent than urokinase and recombinant streptokinase in rabbit models. The OPTIMA-5 trial is an investigator-initiated, prospective, multi-center, randomized, patient blinded, controlled trial comparing a single bolus of half-dose r-SAK with NS in patients with STEMI presenting ≤12 hours of symptom onset and expected to undergo PPCI within 120 minutes. Between October 29, 2021 and August 14, 2022, 283 STEMI patients were screened in 8 centers in China and 200 were randomized to r-SAK group or control in a 1:1 ratio using a computer-generated randomization sequence. On this basis, this study was aimed to conduct a 1-year follow-up study to further confirm the efficacy and safety of this novel reperfusion strategy for patients with STEMI.

Official Title
-----------------
A Single Bolus r-SAK Prior to Primary PCI for ST-elevation Myocardial Infarction (OPTIMA-5): 1-Year Follow-up

Conditions
-----------------
ST-segment Elevation Myocardial Infarction (STEMI)

Intervention / Treatment
-----------------
* Drug: Recombinant Staphylokinase
* Drug: Normal Saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Arm 1 and 2 inclusion and exclusion criteria Inclusion Criteria: Age 18-75 years, weight ≥45 kg; Diagnosed as STEMI (meeting the following two criteria simultaneously): i. Ischemic chest pain lasts ≥30 minutes; ii. Electrocardiogram indicates that ST-segment elevation ≥2 mm in 2 or more contiguous precordial leads or ≥1 mm in 2 or more peripheral leads; Time from onset of persistent chest pain to randomization <12 hours; Primary PCI expected to be performed within 120 minutes. Exclusion Criteria: Cardiogenic shock; Active bleeding or at high risk of bleeding (including grade Ⅲ or Ⅳ retinopathy or retinal gastrointestinal or urinary tract hemorrhage within the past 1 month); Ischemic stroke or TIA in the past 6 months; History of hemorrhagic stroke; Platelet count <100×109/L or hemoglobin <100 g/L; Known intracranial aneurysm; Severe trauma, surgery or head injury within 1 month; Suspected aortic dissection or infective endocarditis; Recent puncture with difficult hemostasis by compression (eg, visceral biopsy, compartment puncture); Currently taking anticoagulants; Poorly controlled hypertension ( ≥180/110 mmHg); Hepatic or renal impairment (glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, or γ -glutamyl transferase >2.5 times upper limit of normal value; creatinine >1.5 times upper limit of normal value); Known allergy to r-SAK; Pregnancy, lactation, or planning for pregnancy; History of myocardial infarction or CABG; Having taken antiplatelet drugs other than aspirin and ticagrelor, such as clopidogrel, prasugrel or cilostazol after the symptom onset; Patients with other conditions that made them unsuitable to be recruited at the discretion of the investigators. Arm 3 inclusion and exclusion criteria Inclusion criteria Age ≥18, ≤75 years old, weight ≥45kg, gender is not limited； Taking maintenance dose of aspirin and ticagrelor for more than 3 days, or taking loading dose of aspirin (300mg) and ticagrelor (180mg); Inpatients with suspected coronary atherosclerotic heart disease scheduled for coronary angiography or interventional therapy. Exclusion criteria Patients who had received r-SAK thrombolytic therapy before; Previous diagnosis of Staphylococcus aureus infection; Patients who were participating in other clinical trials; Other patients considered unsuitable for inclusion by the investigators.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: r-SAK group<br>intravenous injection of single bolus 5 mg r-SAK in 3min | Drug: Recombinant Staphylokinase<br>* Intravenous injection of r-SAK is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction<br>|
| Placebo Comparator: normal saline group<br>intravenous injection of 10ml saline in 3min, r-SAK and saline are the same in appearance | Drug: Normal Saline<br>* Intravenous injection of normal saline is administered within 10 minutes after diagnosis of acute ST-segment elevation myocardial infarction<br>|
| No Intervention: patients with coronary artery disease<br>20 ml arterial blood samples were collected from patients before coronary angiography | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE | A composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, major ventricular arrhythmia | Within 360 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial infarct size measured by CMR | Myocardial infarct size measured by cardiac magnetic resonance (CMR) | Day 360 ± 14 | 
| LVEF measured by CMR | Left ventricular ejection fraction (LVEF) measured by cardiac magnetic resonance (CMR) | Day 360 ± 14 | 
| Angina pectoris assessment: SAQ | Seattle Angina Questionnaire (SAQ). The SAQ consists of 19 items that quantify 5 clinically relevant domains of CAD: physical limitation (question l), angina1 stability (question 2), anginal frequency (questions 3 and 4), treatment satisfaction (questions 5-8), and disease perception (questions 9-11). The higher the score in each dimension, the worse the condition. | Day 360 ± 14 | 
| Health status assessment: EQ-5D | EuroQol Five Dimensions Questionnaire (EQ-5D). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The questionnaire records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. This can be used as a quantitative measure of health outcome that reflect the patient' s own judgement. | Day 360 ± 14 | 
| Heart function assessment: MLHFQ | Minnesota Living Heart Failure Questionnaire (MLHFQ). The MLHFQ includes 21 questions, reflecting how much the patient's heart failure (heart condition) affected their life during the past month (4 weeks). The higher the score in each question, the worse the condition. | Day 360 ± 14 | 
| Adverse cardiac and cerebrovascular events | Each of the above independent MACE events, cardiovascular death, cardiac mechanical complications and stroke. | Within 360 days | 
| NT-proBNP level | N-terminal pro-B-type natriuretic peptide (NT-proBNP) level | Day 360 ± 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ST Elevation Myocardial Infarction, Recombinant Staphylokinase