ABSTRACT
Background
Complete revascularization (CR) has been shown to reduce the risk of adverse cardiovascular events compared with culprit-only revascularization (COR) in acute ST-segment elevation myocardial infarction (STEMI) patients with multivessel disease (MVD). However, the optimal timing of staged complete revascularization (SCR) after primary percutaneous coronary intervention (PCI) remains unclear.
Trial design
The STAGED trial is an investigator-initiated, multicenter, randomized study involving 37 sites, aiming to include 1,586 acute STEMI patients with MVD undergoing successful primary PCI of the culprit lesion followed by SCR. Eligible patients will be assigned to two groups based on the timing of SCR: early-staged PCI and delayed-staged PCI. The primary endpoint is major adverse cardiac event (MACE), including cardiovascular death, myocardial infarction, or ischemia-driven revascularization for both culprit and nonculprit vessels at 12 months since the randomization. The secondary endpoint is individual components of primary endpoint, all-cause death, heart failure-related rehospitalization, stroke, contrast-induced nephropathy, and radiation exposure dose. Follow-up will be conducted through clinic visits or telephone interviews at 1, 3, and 12 months after the index procedure.
Conclusion
The STAGED trial is the first randomized controlled study specifically designed to evaluate the clinical efficacy and safety of different timing strategies for SCR in acute STEMI patients with MVD.
Trial registration
clinicaltrials.gov, NCT04918030.
Background
Multivessel disease (MVD), present in nearly half of patients with ST-segment elevation myocardial infarction (STEMI), is associated with a higher risk of recurrent myocardial infarction, repeat revascularization, and mortality. , In this population, current revascularization strategies include culprit-only revascularization (COR) and complete revascularization (CR). Based on the timing of intervention for nonculprit lesions, CR can be classified into immediate complete revascularization (ICR) and staged complete revascularization (SCR). Randomized controlled trials and meta-analyses have demonstrated that both ICR and SCR reduce the risk of adverse cardiac events compared with COR. ,,,,,,, ICR addresses all lesions during the primary percutaneous coronary intervention (PCI), potentially improving procedural efficiency. However, it carries risks including inaccurate assessment of nonculprit lesion severity, periprocedural myocardial infarction in small vessels, and increased contrast exposure, which may lead to contrast-induced nephropathy. By allowing better lesion assessment and reducing single-procedure time and contrast volume, SCR lowers the risk of periprocedural complications and is consequently more commonly performed in clinical practice. ,,,, The functional assessment of nonculprit lesions is critical for SCR. In this study, we utilized the quantitative flow ratio (QFR), an angiography-based wire-free method, to determine physiological significance. This choice was made because QFR overcomes practical limitations of wire-based indices (e.g., fractional flow reserve) in the acute STEMI setting, such as the need for vasodilators and additional procedural complexity, thereby enhancing patient safety and multicenter feasibility while enabling blinded, standardized core laboratory analysis.
Nevertheless, the optimal timing of SCR in acute STEMI patients with MVD remains unclear.
Several observational studies have investigated the optimal timing of SCR, particularly comparing in-hospital and postdischarge approaches. , Post hoc analyses of the COMPLETE trial suggest that SCR benefits are consistent regardless of whether the procedure is performed during the index hospitalization or after discharge [ . Collectively, these seemingly inconsistent data from observational analyses underscore a significant knowledge gap: while SCR is beneficial, there is a lack of randomized evidence directly comparing specific, well-defined timing strategies to determine which yields superior clinical outcomes. Consequently, we conduct this randomized trial to directly compare in-hospital versus outpatient SCR strategies, aiming to definitively identify the optimal timing of SCR in acute STEMI patients with MVD.
Methods
Study organization
The STAGED trial (clinicaltrials.gov number: NCT04918030) was designed by the principal investigator and the executive committee. The steering and executive committees jointly oversee the trial, ensuring rigorous data analysis and accurate reporting of results. Data are initially collected on paper-based case report forms (CRFs) and subsequently entered into electronic CRFs. To protect participant confidentiality, all submitted data are anonymized, and any ambiguous information is cross-checked against source documents. Two trained investigators and research coordinators review and verify all data, and actively monitor protocol adherence and data accuracy through on-site and remote visits. Patient safety is prioritized, with all serious adverse events meticulously recorded and promptly (within 24 hours) reported to institutional ethics committees. The Data Safety Monitoring Board (DSMB) conducts regular reviews (scheduled at minimum every 6 months, and additionally triggered after 500 patients complete 30-day follow-up or upon accrual of 50% and 75% of primary endpoint events ) to comprehensively assess the safety of staged PCI. The trial is conducted in accordance with the Declaration of Helsinki and has received approval from the institutional ethics committees of all participating centers. Written informed consent is obtained from each participant prior to initiating any study procedures.
The study is funded by Chinese Society of Cardiology’s Foundation (HFCSC2020A03). The funding sources have no role in trial design, data collection, statistical analysis, data interpretation, or manuscript preparation.
Study hypothesis
The study hypothesizes that, in acute STEMI patients with MVD, dealyed SCR of nonculprit lesions is associated with lower MACE than early SCR over a 12-month follow-up.
Study design and study population
This is an investigator-initiated, prospective, multicenter, randomized trial involving 37 cardiac centers. A total of 1,586 acute STEMI patients with MVD requiring staged PCI are planned for enrollment. The study flowchart is presented in Figure 1 .
Study flowchart. A total of 1,586 acute STEMI patients with MVD who have successfully undergone culprit-lesion revascularization are randomly assigned in a 1:1 ratio to undergo early-staged PCI or delayed-staged PCI. The primary endpoint is MACE at 12 months after the index procedure.
This study includes acute STEMI patients with MVD who underwent successful primary PCI of the culprit lesion, achieving final TIMI flow 3, residual stenosis <20%, and no angiographic evidence of type B or higher coronary dissection. If immediate postprocedure TIMI flow is suboptimal (< grade 3), repeat angiography is performed within 24 hours, and patients achieving TIMI flow 3 at that time remain eligible. Coronary angiography must confirm multivessel disease, with at least one de novo lesion in a nonculprit epicardial vessel showing ≥80% diameter stenosis by visual estimation, a reference vessel diameter ≥2.5 mm, and a quantitative flow ratio (QFR) ≤0.80. All participants, or their legally authorized representatives, provide written informed consent after being fully informed of the study objectives, procedures, potential risks, and benefits.
The main exclusion criteria are as follows: (1) Presence of cardiogenic shock, multiple organ failure, cerebral hemorrhage, severe aortic valve stenosis, or acute mechanical MI complications (cardiac rupture, ventricular septal perforation, papillary muscle rupture) on admission; (2) Cardiogenic shock, Killip class >III, or recurrent infarction of the culprit vessel within 24 hours after primary PCI; (3) Planned surgery within 6 months that may interfere with continuous antiplatelet therapy; (4) Anticipated death from any cause within 12 months. Tables 1 and 2 summarize the detailed inclusion and exclusion criteria.
Table 1
Inclusion criteria.
| 1. The participants or their legal guardians should have a thorough understanding of the trial’s design and treatment procedures. Written informed consent must be obtained before conducting any trial-specific tests or procedures. |
| 2. Established indication to PCI according to the guidelines of American Heart Association and American College of Cardiology. |
| 3. Spontaneous acute STEMI (patients presenting within 24 hours of symptom onset) with MVD after successful revascularization of the culprit lesion. |
| 4. De novo coronary lesion. |
| 5. TIMI flow 3 (Cases with TIMI flow 2 need to perform angiographic again in 24h ensured TIMI flow 3 for enrolling case) after revascularization of the culprit artery, residual stenosis ≤20% and no coronary dissection greater than or equal to type C leading to (threatening) vessel closure. |
| 6. At least one nonculprit coronary stenosis ≥ 80% and accompanied by QFR ≤0.8 in a vessel with a lumen diameter ≥2.5mm. |
PPCI , primary percutaneous coronary intervention; STEMI , ST-segment elevation myocardial infarction; MVD , multivessel disease; TIMI , thrombolysis in myocardial infarction; QFR , quantitative flow ratio.
Table 2
Exclusion criteria.
| 1. Age < 18 years or > 80 years. |
| 2. Presence of cardiogenic shock, multiple organ failure, cerebral hemorrhage, severe aortic valve stenosis, or acute mechanical complications of myocardial infarction (cardiac rupture, ventricular septal perforation, papillary muscle rupture) at the time of emergency admission. |
| 3. Cardiogenic shock, Killip class > III, or recurrent infarction of the culprit vessel within 24 hours after the index PCI. |
| 4. Planned surgery within 6 months that may interfere with continuous antiplatelet therapy. |
| 5. Participation in another clinical trial involving coronary interventional devices. |
| 6. Anticipated death from any cause within 12 months. |
| 7. Inability to comply with the study protocol or, in the opinion of the investigator, participation in the study would increase risk to the subject. |
PCI , percutaneous coronary intervention.
Randomization and masking
Patients who achieve successful revascularization of the culprit lesion will have their angiographic data uploaded to the core laboratory within 24 hours for eligibility assessment. Patients with postprocedural TIMI flow less than grade 3 undergo repeat angiography within 24 hours; images achieving TIMI flow 3 may be submitted within 48 hours of the index procedure. Eligible patients were randomized through an interactive web-based system in a 1:1 ratio to eitherearly-staged PCI group or delayed-staged PCI group, with allocation stratified by site using dynamic minimization. Early-staged PCI is scheduled within 7 ± 3 days after the index primary PCI, while delayed-staged PCI is planned at 30 ± 15 days postdischarge. Study Design Diagram is presented in Figure 2 . Patients with diabetes mellitus or left main coronary artery disease was considered high-risk, and stratification will be performed based on the presence or absence of these conditions. Due to the nature of staged PCI procedures and differences in clinical pathways, physicians in the catheterization laboratory and inpatient healthcare staff could not be blinded to treatment allocation. To minimize potential observational bias, outcome assessors, follow-up personnel, and data analysts remained blinded to group assignments throughout the study. Randomization at each participating center was independently conducted by a study coordinator not involved in clinical care or data collection, ensuring allocation independence and maintaining study rigor.
Study design diagram. STEMI: ST-segment elevation myocardial infarction; MVD , multivessel disease; SCR , staged complete revascularization; PCI , percutaneous coronary intervention; QFR , quantitative flow ratio; CAG , coronary angiography; TIMI , thrombolysis in myocardial infarction.
Study implementation and percutaneous coronary intervention
After successful culprit vessel revascularization (defined as TIMI flow grade 3, residual stenosis <20%, and no ≥Type B dissection), angiograms for patients with MVD will be uploaded to the core lab within 48h for the measurements of QFR. For patients with TIMI flow <3 postculprit vessel PCI, repeat coronary angiography will be performed within 24h to make sure if the flow has recovered to grade 3, if yes, angiograms will be delivered for QFR measurement within next 24 h. Detailed protocols for QCA and QFR are provided in the Appendix 1.
All interventional procedures were performed in accordance with the guidelines of American Heart Association and American College of Cardiology . , patients are recommended to chew 300 mg of aspirin and at least 180 mg of ticagrelor. During the procedure, unfractionated heparin will be administered to maintain an activated clotting time (ACT) > 280 seconds. Creatine kinase (CK), CK-MB, and cardiac troponin levels will be routinely monitored within 48 hours postprocedure to assess myocardial injury. After PCI, aspirin (100 mg once daily) will be prescribed for lifelong use, and clopidogrel (75 mg once daily) or ticagrelor (90 mg twice daily) will be recommended for 12 months as part of dual antiplatelet therapy.
