Rationale and design of the OPTIMAL‐REPERFUSION trial: A prospective randomized multi‐center clinical trial comparing different fibrinolysis‐transfer percutaneous coronary intervention strategies in acute ST‐segment elevation myocardial infarction

Abstract Primary percutaneous coronary intervention (PPCI), the preferred reperfusion strategy for all acute ST‐segment elevation myocardial infarction (STEMI) patients, is not universally available in clinical practice. Pharmacoinvasive strategy has been proposed as a therapeutic option in patients with STEMI when timely PPCI is not feasible. However, pharmacoinvasive strategy has potential delay between clinical patency and complete myocardial perfusion. The optimal reperfusion strategy for STEMI patients with anticipated PPCI delay according to current practice is uncertain. OPTIMAL‐REPERFUSION is an investigator‐initiated, prospective, multicenter, randomized, open‐label, superiority trial with blinded evaluation of outcomes. A total of 632 STEMI patients presenting within 6 hours after symptom onset and with an expected time of first medical contact to percutaneous coronary intervention (PCI) ≥120 minute will be randomized to a reduced‐dose facilitated PCI strategy (reduced‐dose fibrinolysis combined with simultaneous transfer for immediate invasive therapy with a time interval between fibrinolysis to PCI < 3 hours) or to standard pharmacoinvasive treatment. The primary endpoint is the composite of death, reinfarction, refractory ischemia, congestive heart failure, or cardiogenic shock at 30‐days. Enrollment of the first patient is planned in March 2021. The recruitment is anticipated to last for 12 to 18 months and to complete in September 2023 with 1 year follow‐up. The OPTIMAL‐REPERFUSION trial will help determine whether reduced‐dose facilitated PCI strategy improves clinical outcomes in patients with STEMI and anticipated PPCI delay. This study is registered with the ClinicalTrials.gov (NCT04752345).


| INTRODUCTION
Early and successful restoration of myocardial perfusion after a STelevation myocardial infarction (STEMI) is the most effective way to reduce the final infarct size and improve clinical outcomes. It is generally well-accepted that primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for all STEMI patients when it can be performed within the guideline-recommended time frame at PPCIcapable centers. 1,2 However, PPCI is not universally available, and delay in performing percutaneous coronary intervention (PCI) is common in clinical practice, especially in low-and middle-income countries. [3][4][5] Pharmacoinvasive strategy, fibrinolysis combined with rescue PCI (in case of failed fibrinolysis) or routine early (3-24 hours) invasive strategy (in case of successful fibrinolysis), has been proposed as a therapeutic option for STEMI patients when timely PPCI is not feasible. 1,2 However, there is a potential time delay between clinical patency and complete myocardial perfusion in pharmacoinvasive strategy. Successful clinical reperfusion does not mean a good flow grade of thrombolysis in myocardial infarction (TIMI) and tissue perfusion. Studies have revealed that the proportion of TIMI flow grade < 3 confirmed by coronary angiography in patients with clinical patency was as high as 50%. [6][7][8] Moreover, the re-occlusion of the infarct-related artery (IRA) and recurrent ischemia rate in clinical patency patients while waiting for PCI is high (nearly 30%). 9 The optimal timing of coronary angiography after fibrinolysis is uncertain. 10 Facilitated PCI strategy (fibrinolysis followed by immediate transfer for planned PCI within 90 to 120 minutes) can maximally reduce time delay, enable early treatment of patients with potential fibrinolysis failure and reinfarction of successful fibrinolysis, and thus theoretically achieve better outcomes. Previous studies demonstrated that facilitated PCI could significantly improve the clinical outcomes of STEMI patients compared with thrombolytic therapy. 11,12 Additionally, this strategy acquired significantly higher TIMI flow grade of IRA and better microcirculation perfusion compared with PPCI. 13 However, increased bleeding risk, especially intracranial bleeding, became its Achilles' Heel and limited its clinical application. To date, no randomized clinical trial directly compared the regimen of facilitated PCI and pharmacoinvasive approach. 14 Table S1. The specific requirements of the sub-centers are shown in the Appendix S1. Each selected sub-center will compete for enrollment and each sub-center will have a maximum enrollment of 60 cases. A flowchart depicting the trial design is shown in Figure 1. Given the apparent difference in time of transfer and invasive procedure between the two regimens, it will not be possible to blind the subjects and operators as to which strategy the patients will undergo. To minimize potential bias, a robust inclusion/exclusion criteria and clear endpoint definitions and boundaries will be used. Any deviation from the protocol in delivery of strategy will be carefully recorded, including any concomitant therapies. The protocol has been approved by institutional review boards in all participating centers. Written informed consent will be obtained from all participants (see Appendix S1).

| Patients
STEMI patients between 18 and 75 years of age who present within 6 hours after symptom onset to participating PCI-incapable primary hospital and with an expected first medical contact (FMC) to PCI time ≥ 120 minute will be screened for study eligibility.
Patients must have ≥2 mm ST-segment elevation in 2 contiguous precordial leads, ≥1 mm ST-segment elevation in 2 contiguous extremity leads, or new left bundle branch block with symptom onset persisting for more than 30 minute. Key exclusion criteria included any contraindication for fibrinolysis, cardiogenic shock before randomization, PCI within last 6 months, and previous coronary-artery bypass surgery. A complete list of the exclusion criteria is provided in Table S2.

| Randomization
Patients who satisfy the inclusion and exclusion criteria will be randomly assigned in a 1:1 fashion to either a ''reduced-dose facilitated PCI group'' or ''pharmacoinvasive group''. Randomization is performed through an Interactive Web-based Response System, which will be implemented to assign a randomization number to an eligible patient as well as to track enrollment across all centers, with a permuted block randomization scheme stratified by the time interval between disease onset and enrollment (less than 3 hours and 3-6 hours).

| Treatment
All patients will receive an upfront loading dose of 300 mg aspirin and 300 mg clopidogrel in the emergency room of non-PCI medical institutions. Potent adenosine diphosphate (ADP) receptor antagonists, prasugrel, and ticagrelor are not recommended. Patients who have already taken aspirin or ADP receptor antagonists ≤12 hours before screening will be given these agents on the following day. GPI use is not allowed before PCI. The bailout uses of GPI in the catheter lab or post-catheterization is at the operator's discretion. Routine anticoagulation therapy after PCI is not recommended. Recombinant human prourokinase (rhPro-UK, Tasly Pharmaceuticals, Shanghai, China), a urokinase precursor that represents a new generation of fibrin-specific thrombolytic drugs with relatively few adverse reactions, 15 is the thrombolytic agent used in both regimen groups. Comedication consists of unfractionated heparin given as 60 U/kg (up to a maximum of 4000 U) bolus before the thrombolytic agent and will be maintained at 12 U/kg/h (up to a maximum of 1000 U/h) until the catheterization. For coronary angiography, the radial-artery approach is preferred. During the invasive procedure, an additional intravenous bolus of heparin could be administered if needed to obtain an activated clotting time of 200 to 250 seconds. Beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and postinterventional antiplatelet therapy will be administered to patients as outlined in the guidelines for myocardial infarction. 2

| Pharmacoinvasive group
Enrolled patients will be injected with 20 mg rhPro-UK intravenously followed by intravenous infusion of 30 mg rhPro-UK within 30 minute F I G U R E 1 The flow chart of the study. FMC, first medical contact; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction in the emergency department of non-interventional hospitals. Transfer to a PCI-capable center following fibrinolysis is indicated for all patients immediately after fibrinolysis. In case of insufficient ST resolution (less than 50% reduction in ST-segment elevation) at 60-90 minute or clinically indicated by the presence of hemodynamic or electrical instability, or worsening ischemia, rescue PCI will be taken. Early routine catheterization within 3-24 hours for successful fibrinolysis will be performed.
PCI will be performed when persistent occlusion or substantial stenosis of the IRA (either stenosis of ≥70% of the diameter of the artery or stenosis of 50% to 70% with thrombus, ulceration, or spontaneous dissection) is present. Direct stent implantation and new generation of drugeluting stents are recommended, and routine post-dilation is not encouraged [16][17][18] unless there is an obvious stent under-expansion.

| Reduced-dose facilitated PCI group
Patients randomly assigned to the ''reduced-dose facilitated PCI group'' will immediately start reduced-dose thrombolysis treatment (intravenous injection of 20 mg rhPro-UK followed by intravenous infusion of 10 mg rhPro-UK within 30 minute) with simultaneous transfer to a PCI center through an affiliated ambulance of the participating local hospital. En route, participating non-PCI center and PCI center will be contacted to confirm the potential feasibility of transfer and immediate PCI upon arrival. When arriving at the PCI centers, bypassing the emergency department will be strongly recommended and the patient will be brought straight to the catheterization laboratory, and immediate coronary angiography and angioplasty will be performed. The requirements of stent implantation are the same as the ''pharmacoinvasive group''.

| Primary endpoint
The primary endpoint of the trial is the composite of death, reinfarction, refractory ischemia, congestive heart failure, and cardiogenic shock at 30-days. Definitions of the end points are provided in Table 1.

Endpoint Definition
Death Death will be classified as cardiovascular or non-cardiovascular. All deaths with a clear cardiovascular or unknown cause, will be classified as cardiac. However, within cardiac deaths, hemorrhagic deaths will be clearly identified. Only deaths due to a documented non-cardiac cause (e.g., cancer) will be classified as non-cardiac.

Reinfarction
Recurrent symptoms or signs of cardiac ischemia lasting more than 30 min with new ST-T segment changes or Q-wave in at least 2 contiguous leads or new onset LBBB and recurrent significant increase in cardiac enzyme levels. The increase in CK-MB level is considered significant when it occurs after at least a ≥ 25% decrease in CK-MB from a prior peak level and is >2 times the upper limit of normal (ULN) in the absence of coronary interventions, or > 5 times above the ULN after PCI.
Refractory ischemia Symptoms of ischemia with ST-deviation or definite T-wave inversion persisting for at least 10 min despite enough antianginal drug occurring more than 12 hr after randomization.

Congestive heart failure
New or worsening congestive heart failure will be considered as patients presenting with at least one of the following conditions and requiring treatment with diuretics: 1) Pulmonary oedema/congestion on chest X-ray without suspicion of a non-cardiac cause; 2) Rales >1/3 up from the lung base; 3) Pulmonary capillary wedge pressure (PCWP) >25 mmHg; 4) Dyspnea with PO 2 < 80 mmHg or O 2 sat < 90% (no supplemental O 2 ) in the absence of known lung disease.

Cardiogenic shock
The manifestation of vascular collapse and shock (systolic BP < 90 mmHg for at least 30 min or systolic BP > 90 mmHg after inotropic or intra-aortic balloon support with a cardiac index <2.2 L/min/m 2 or < 2.5 L/min/m 2 after inotropic or intra-aortic balloon support, peripheral signs of hypoperfusion, and chest X-ray with pulmonary edema.

Major ventricular arrhythmia
Ventricular arrhythmias, occurring more than 6 hr after randomization, persisting for at least 30 sec, and accompanying with unstable hemodynamics that required electrical cardioversion/defibrillation.

Ischemia stroke
Defined as the presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting more than 24 hr. It is strongly recommended (but not required) that an imaging procedure, such as, a computerized tomography (CT) or magnetic resonance imaging (MRI) be performed.  Definitions of the endpoints are provided in Table 1.

| Safety endpoint
The primary safety endpoint is the incidence of intracranial hemorrhage and major bleeding. All bleeding complications are classified using the Bleeding Academic Research Consortium (BARC) definition. 20 Major bleeding is categorized as type 3 or 5 (type 3 indicating bleeding with a decrease in the hemoglobin of >3 g per deciliter, any transfusion, cardiac tamponade, or intracranial or ocular involvement; and type 5 indicating fatal bleeding). All bleeding needs to describe the bleeding site. admissions for cardiovascular problems in the first year after STEMI will be collected. The patients will register their use of health resources between each follow-up. Health-related quality of life will be collected at baseline and at each follow-up visit and will be measured with EQ-5D questionnaire.

| Follow-up
All study participants will be followed up at 30 ± 5 days and 1 year ±30 days after enrolment. Telephone follow-up will be obtained at 14 ± 3 days and 90 ± 14 days after enrolment. At 180 ± 30 days, a telephone or site follow-up visit will be carried out. The data collection and monitoring are shown in the Appendix S1. Clinical endpoints will be adjudicated by a clinical events committee blinded to treatment group assignment.

| Sample size
The sample size is estimated based on the primary study endpoint.
The primary endpoint event definitions and rate for the ''pharmacoinvasive group'' was estimated according to WEST (Which Early STEMI Therapy) study, 21 in which, the 30-day composite primary event (death 1%, reinfarction 5.8%, refractory ischemia 2.9%, congestive heart failure 14.4%, cardiogenic shock 3.8%) occurred in 24% of patients in the pharmacoinvasive group.
On the basis of the potential fibrinolysis failure rate is 30%-40%, 22 and the early re-occlusion and recurrent ischemia rate after initial successful fibrinolysis is as high as 30% in the standard therapy group, 9 the expected relative risk reduction in the primary end point with ''reduced-dose facilitated PCI group'' relative to the standard therapy group was estimated as 40% (14.4% for the event rate). With a power of 85% and a 2-sided alpha of 0.05, the required sample size is 301 patients per group, for a total sample size of 601 patients. With an anticipated loss to follow-up of approximately 5%, the target sample size was set at 632 patients. Moreover, sample size re-estimation will be conducted when approximately 50% of participants have been recruited (Appendix S1).

| Statistical analysis
Primary trial analyses will be intention to treat (ITT) and additional analyses will also be done on the per protocol population (PP). ITT population consists of all randomized subjects with valid informed consent. PP population is a subset of the ITT population in which subjects with major protocol deviations will be excluded. Protocol deviations will be defined in the statistical analysis plan.
A log binomial model (a generalized linear model [GLM]) will be used to analyze the primary endpoint. The GLM will include the treatment arm as the study variable, from which the relative risk (RR) of having a primary outcome between intervention and control together with 95% confidence interval (CI) will be derived. Covariate adjusted analysis of the primary endpoint will also be performed within the GLM framework with treatment arm as the study variable and the time to randomization, sex, weight, systolic blood pressure, infarct location, Killip class, and a history of diabetes or hypertension as covariates. Adjusted RR together with their 95% CI will be derived from the covariate adjusted GLM model. Subgroup analysis will also be performed for the above pre-specified covariates.
The secondary binary and continuous outcomes will be analyzed similarly using GLM models. For GLM analysis of a continuous endpoint such as left ventricular function, normal distribution and identity link functions will be used; For GLM analysis of a binary outcome, (such as, having a primary endpoint), binomial distribution and log link functions will be used.
For the analysis of time-to-event outcome, the Kaplan-Meier curves will be presented and compared by the log rank test by treatment group, and hazard ratio and its 95% CI will be calculated using Cox regression model with the treatment arm as the study variable. Generalized linear mixed model (GLMMIX) model will be employed to analyze the outcomes with repeated measurements. The model will have treatment, visit, interaction between treatment and visit as fixed effects, and subjects as random effect. For the analysis of binary secondary outcomes with repeated measurements, the GLMMIX model will have a binomial distribution and logit link function. The odds ratio between 2 treatment arms at each visit together with its 95% CI will be derived from the GLMMIX model. For the analysis of continuous secondary outcomes with repeated measurements, the GLMMIX model will have a normal distribution and identify link function. The mean difference between 2 treatment arms at each visit together with its 95% CI will be derived from the GLMMIX model.
Continuous variables will be summarized using number of observations, mean (standard deviation) or median (inter quartile range) as appropriate; categorical variables will be summarized by the number and percentage of events. Time-to-event variables will also be summarized by the number (%) of patients having an event and events per 100 person-years by treatment arm. Analyses of the potential adverse effects of the test strategy will be done in the safety population.
All analyses will be described in detail in the statistical analysis plan. All statistical analyses will be performed using the SAS 9.4. The trial results will be reported following the Consolidated Standards of Reporting Trials (CONSORT) guidelines for randomized clinical trials.

| Trial status
The trial is now actively preparing at West China Hospital of Sichuan University and other sub-centers. The first patient will be planned to enroll in March 2021. The recruitment will last for 12 to 18 months and is planned to complete in September 2022.

| DISCUSSION
In countries and areas, with large, sparse population and not well- Since the publication of these trials, significant advances have occurred in pharmacological therapy and PCI technology. Therefore, in patients with STEMI presenting in non-PCI centers and with anticipated PPCI delay, fibrinolysis followed by very early angiography (<2 to 3 hours) may be a feasible strategy according to current practice.
Moreover, many studies demonstrated that approximately 50% of the successful fibrinolysis patients of standard pharmacoinvasive strategy did not achieve optimal perfusion (TIMI flow grade 3), [6][7][8]23,26,30 not to mention patients of failed fibrinolysis, and very early revascularization is of great clinical significance for these suboptimal perfusion patients, whom might potentially benefit from the reduced-dose facilitated PCI strategy.
The antithrombotic regimen in OPTIMAL-REPERFUSION includes both aspirin, clopidogrel, and heparin on top of rhPro-UK. This antithrombotic regimen is more aggressive than the regimen used in the test arm of the ASSENT-4 PCI trial, which noted more ischemic complications than PPCI group. Moreover, the reduced-dose rhPro-UK in the test arm of OPTIMAL-REPERFUSION trial, combined with routine use of radial-artery access and bailout use of GPI, aims to reduce bleeding risk.
In conclusion, the OPTIMAL-REPERFUSION study is designed to provide important information on whether reduced-dose facilitated PCI strategy is safe, cost-effective, and superior to the standard pharmacoinvasive approach with 3 to 24 hours invasive regimen.