European Journal of Cardiovascular Medicine

ST-elevation myocardial infarction (STEMI) is a time-sensitive clinical emergency characterized by complete occlusion of a coronary artery, often resulting in transmural myocardial necrosis if not rapidly reperfused. While primary percutaneous coronary intervention (PCI) is the gold standard for reperfusion in STEMI, many healthcare systems, particularly in low- and middle-income countries, face logistical barriers that delay timely PCI. In such contexts, a pharmacoinvasive strategy—comprising fibrinolysis followed by planned PCI within 3 to 24 hours—has emerged as a pragmatic and evidence-based approach to achieve timely reperfusion and improve outcomes【1,2】.

One of the key determinants of successful reperfusion and myocardial salvage is the restoration of Thrombolysis in Myocardial Infarction (TIMI) grade III flow in the infarct-related artery (IRA). TIMI flow grade serves as a surrogate for epicardial perfusion, and suboptimal flow (≤ TIMI II) post-PCI is associated with increased infarct size, adverse left ventricular remodeling, and higher mortality【3,4】. However, even in cases where mechanical reperfusion is achieved, a subset of patients fails to demonstrate effective myocardial perfusion due to microvascular obstruction, known as the no-reflow phenomenon. This complication remains a significant predictor of in-hospital and long-term adverse cardiac events【5】.

The incidence of no-reflow has been variably reported to range between 5–30% depending on infarct location, thrombus burden, PCI technique, and most importantly, the timing of intervention【6,7】. Anterior wall STEMI, due to the large myocardial territory at risk and greater thrombotic burden in the left anterior descending artery (LAD), is particularly prone to no-reflow and post-PCI TIMI flow impairment【8】. Although pharmacoinvasive PCI aims to reduce infarct size and improve coronary flow, the optimal timing of PCI post-thrombolysis to minimize no-reflow and achieve maximal TIMI III flow remains incompletely defined.

Earlier intervention (e.g., within 6–10 hours) has been hypothesized to reduce thrombus load before full organization and enhance microvascular preservation, thus promoting higher TIMI III flow post-procedure【9】. Conversely, delayed PCI beyond 18–24 hours may result in increased infarct stiffness, organized thrombus, distal embolization, and endothelial dysfunction, all of which contribute to impaired perfusion and no-reflow【10】. However, early PCI may also be complicated by hemorrhagic risks due to residual fibrinolytic activity.

Several pivotal clinical trials have examined the timing of PCI following thrombolysis in patients with ST-elevation myocardial infarction (STEMI), particularly focusing on angiographic success and the incidence of the no-reflow phenomenon. The STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial was a landmark study that randomized early presenters with STEMI to receive either prehospital tenecteplase followed by PCI within 6–24 hours or immediate primary PCI. The study demonstrated non-inferiority of the pharmacoinvasive strategy, with comparable 30-day outcomes and high rates of TIMI III flow in the pharmacoinvasive group (89%) 【11】. Similarly, the TRANSFER-AMI trial, which included over 1,000 patients, showed that immediate transfer for PCI within 6 hours after tenecteplase administration significantly reduced the composite outcome of death, reinfarction, heart failure, and cardiogenic shock compared to standard care, with better angiographic outcomes in the early PCI group 【12】. The CARESS-in-AMI trial supported these findings, revealing that early PCI within 3–12 hours post-fibrinolysis resulted in lower reinfarction and ischemia rates compared to a conservative approach, alongside improved TIMI III flow 【13】. The GRACIA-1 trial provided further evidence that a routine invasive strategy within 24 hours of thrombolysis significantly reduced major adverse cardiac events (MACE) compared to an ischemia-guided approach 【14】. The WEST trial, though underpowered, demonstrated that early PCI following thrombolysis was associated with high rates of optimal reperfusion and outcomes comparable to primary PCI 【15】. Additionally, the CAPTIM trial emphasized the importance of time-to-treatment, showing that patients treated with prehospital fibrinolysis followed by PCI had better survival if treated within 2 hours of symptom onset 【16】. Notably, Elhefny et al. conducted a prospective study focusing specifically on anterior STEMI patients undergoing PCI at different time intervals post-streptokinase thrombolysis. They found that patients treated within 3–10 hours had the highest LVEF at 6 months and the lowest rates of no-reflow and in-hospital mortality, highlighting the benefit of early intervention 【17】. Collectively, these trials underscore the importance of optimizing the timing of PCI following thrombolysis, particularly in anterior STEMI, to maximize myocardial reperfusion and reduce complications such as no-reflow.

In this study, we aimed to assess the influence of timing of pharmacoinvasive PCI on angiographic success, measured by pre- and post-procedural TIMI flow grades, and the incidence of no-reflow phenomenon in patients presenting with anterior STEMI. By stratifying patients into three PCI timing groups post-thrombolysis (3–10 h, 10–17 h, and 17–24 h), we sought to identify the optimal window for intervention that maximizes perfusion efficacy and minimizes procedural complications in a real-world, high-risk STEMI cohort.

Study Design and Setting

This was a prospective, observational cohort study conducted at the Department of Cardiology, Government Medical College, Thiruvananthapuram, Kerala, India. The study enrolled patients over a 1-year period following ethical approval from the Institutional Ethics Committee (IEC).

Study Population

The study included adult patients (≥18 years) presenting with acute anterior wall ST-segment elevation myocardial infarction (AW-STEMI), diagnosed by clinical criteria and electrocardiographic findings, who received fibrinolysis followed by planned pharmacoinvasive PCI within 24 hours. Written informed consent was obtained from all participants prior to enrollment.

Inclusion Criteria

• Patients diagnosed with anterior wall STEMI who underwent thrombolysis (either with streptokinase or tenecteplase).
• Underwent planned PCI within 24 hours of fibrinolytic therapy.
• Age ≥18 years.
• Provided informed consent.

Exclusion Criteria

• Patients undergoing rescue PCI due to failed thrombolysis.
• Cardiogenic shock at presentation (systolic BP <80 mmHg unresponsive to fluid resuscitation or requiring vasopressors).
• History of myocardial infarction within the preceding 6 months.
• History of previous coronary artery bypass graft (CABG) surgery.
• Patients unable to comply with study protocols or those who declined consent.

Study Groups

Eligible patients were stratified into three groups based on the time interval between thrombolysis and PCI:

• Group A: PCI performed within 3–10 hours post-thrombolysis
• Group B: PCI performed within 10.1–17 hours post-thrombolysis
• Group C: PCI performed within 17.1–24 hours post-thrombolysis

Clinical and Angiographic Assessment

All patients underwent baseline clinical evaluation, electrocardiography, routine laboratory investigations, and echocardiographic assessment. Coronary angiography was performed using standard techniques, and PCI was carried out according to current institutional protocols.

The TIMI (Thrombolysis In Myocardial Infarction) flow grade was assessed both before and after PCI by experienced interventional cardiologists who were blinded to the study group allocation. TIMI flow was graded as follows:

• Grade 0: No perfusion
• Grade 1: Penetration without perfusion
• Grade 2: Partial perfusion
• Grade 3: Complete perfusion

The no-reflow phenomenon was defined as post-PCI TIMI flow <3 in the absence of mechanical obstruction, dissection, or spasm.

Outcome Measures

The primary outcome measures were:

• Pre-procedural TIMI flow grades
• Post-procedural TIMI flow grades
• Incidence of no-reflow phenomenon

Secondary analyses included associations between PCI timing groups and final angiographic outcomes.

Data Collection and Management

Data were collected using a structured case record form at the time of admission and during angiographic intervention. Demographic data, cardiovascular risk factors, infarct-related artery (IRA), lesion characteristics, and number of stents deployed were documented. TIMI flow grades were recorded from angiographic reports.

Statistical Analysis

Data were analyzed using IBM SPSS version 26.0 (IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) and compared using one-way ANOVA. Categorical variables, including TIMI flow grades and no-reflow rates, were compared using the Chi-square test or Fisher’s exact test, as appropriate. A p-value <0.05 was considered statistically significant.

Baseline charecteristics.

A total of 480 patients with anterior wall STEMI who received thrombolysis and underwent pharmacoinvasive PCI within 24 hours were included. The cohort was stratified into three groups based on the time interval from thrombolysis to PCI: Group A (3–10 hours, n = 174), Group B (10.1–17 hours, n = 156), and Group C (17.1–24 hours, n = 150).

Pre-Procedural TIMI Flow

Baseline angiographic assessment revealed no significant difference in pre-procedural TIMI flow grades among the three groups (p = 0.998). TIMI 0 flow was observed in 29.9% of patients in Group A, 33.3% in Group B, and 31.3% in Group C. TIMI I flow was the most common in all groups, noted in 36.8%, 35.3%, and 36.0%, respectively. Pre-PCI TIMI III flow was achieved in only a small fraction of patients across the groups (13.2%, 12.2%, and 13.3%, respectively).

Post-Procedural TIMI Flow

Post-PCI angiographic outcomes demonstrated higher rates of optimal reperfusion (TIMI III flow) in patients who underwent earlier intervention. TIMI III flow was achieved in 96.0% of patients in Group A, compared to 91.7% in Group B and 90.7% in Group C. Although this difference did not reach statistical significance (p = 0.135), a clear numerical trend favored earlier PCI. Conversely, TIMI II flow—indicative of suboptimal reperfusion—was more frequent in Group C (9.3%) and Group B (8.3%) compared to Group A (4.0%).

No-Reflow Phenomenon

The incidence of the no-reflow phenomenon, defined as post-PCI TIMI flow <3 in the absence of mechanical obstruction, was lowest in Group A (4.0%), followed by Group B (8.3%) and Group C (9.3%). While the differences were not statistically significant, this trend suggests a potential protective effect of early PCI against microvascular obstruction and no-reflow.

In this prospective observational study of anterior STEMI patients managed via a pharmacoinvasive strategy, we evaluated the impact of PCI timing following thrombolysis on coronary flow outcomes, specifically pre- and post-procedural TIMI flow grades and the incidence of no-reflow. Our findings suggest that earlier intervention—particularly within 3 to 10 hours of thrombolysis—is associated with a numerically higher likelihood of achieving post-PCI TIMI III flow and a lower incidence of no-reflow, though the differences did not reach statistical significance.

TIMI flow grade remains a robust angiographic surrogate for myocardial perfusion and clinical prognosis following STEMI. Restoration of TIMI III flow has been associated with improved left ventricular function, reduced infarct size, and lower rates of mortality and adverse events【18】. In our study, patients who underwent PCI within 3–10 hours of thrombolysis achieved TIMI III flow in 96% of cases, compared to 91.7% and 90.7% in the 10.1–17 hour and 17.1–24 hour groups, respectively. These findings are consistent with prior literature suggesting that early mechanical reperfusion, even after fibrinolysis, is crucial for effective myocardial salvage【19】.

The incidence of no-reflow—a phenomenon resulting from microvascular obstruction despite open epicardial arteries—was lowest in the earliest PCI group (4.0%), compared to 8.3% and 9.3% in the intermediate and late groups. This aligns with existing data suggesting that delayed PCI may predispose patients to microvascular damage, distal embolization, and endothelial dysfunction, all of which contribute to impaired myocardial perfusion【20,21】. The lower thrombus burden and preserved microcirculation observed in early presenters may underlie this protective effect.

Our findings are supported by the results of the TRANSFER-AMI trial, which demonstrated that immediate transfer for PCI within 6 hours post-tenecteplase led to improved composite outcomes, including reinfarction and cardiogenic shock, with better post-procedural TIMI III flow rates【12】. Similarly, the STREAM trial showed that a pharmacoinvasive approach with PCI performed between 6 and 24 hours after prehospital thrombolysis resulted in clinical outcomes comparable to primary PCI, with acceptable rates of angiographic success【11】.

Further insights can be drawn from the CARESS-in-AMI trial, which reported that early PCI (within 3 to 12 hours) after thrombolysis significantly reduced refractory ischemia and reinfarction compared to a conservative strategy【13】. Although our study did not observe statistically significant differences in TIMI III flow or no-reflow incidence across groups, the consistent directional trend reinforces the concept that early pharmacoinvasive PCI is more likely to achieve favorable coronary flow.

Interestingly, the study by Elhefny et al. specifically evaluated anterior STEMI patients and showed that PCI within 3–10 hours post-streptokinase led to better preservation of LVEF and reduced in-hospital mortality, supporting our observation that anterior infarctions derive particular benefit from timely intervention due to the larger myocardial territory at risk【17】. In contrast, deferral of PCI beyond 17 hours, although still within guideline-recommended windows, may allow progression of thrombus organization and microvascular injury, potentially limiting the success of revascularization.

The clinical implications of our findings are relevant for regions where primary PCI is not universally available and thrombolysis remains the initial reperfusion strategy. Structured pharmacoinvasive protocols, emphasizing prompt transfer for angiography within the early post-lysis window, may improve procedural outcomes and reduce complications such as no-reflow. Moreover, our study provides real-world evidence in the context of anterior STEMI—a subset known for higher thrombus burden and poorer outcomes.

LIMITATIONS

This study has several limitations. First, it is observational in nature and may be subject to unmeasured confounding. Second, the assessment of TIMI flow was operator-reported, which may introduce variability. Third, while the trends in no-reflow and TIMI flow favor early PCI, the lack of statistical significance may be due to sample size limitations or relatively low event rates. Finally, advanced imaging modalities such as myocardial blush grade or cardiac MRI, which offer more granular insights into microvascular perfusion, were not employed.

In conclusion, our study highlights that earlier pharmacoinvasive PCI, particularly within 3–10 hours of thrombolysis, is associated with a higher likelihood of achieving optimal post-procedural TIMI III flow and a lower incidence of no-reflow in patients with anterior STEMI. These findings support the ongoing need for timely triage and structured transfer protocols following fibrinolysis, especially in settings where primary PCI access is limited.

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18. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000;101(2):125–130. doi:10.1161/01.CIR.101.2.125
19. Stone GW, Peterson MA, Lansky AJ, et al. Impact of TIMI flow grade on mortality in patients with acute coronary syndromes. Am J Cardiol. 2005;95(11):1362–1366. doi:10.1016/j.amjcard.2005.01.062
20. Rathod KS, Jones DA, Rathod VS, et al. Optimal timing of intervention in the pharmacoinvasive approach to STEMI: a meta-analysis. Heart. 2017;103(17):1471–1477. doi:10.1136/heartjnl-2016-310952
21. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation. 2002;105(5):656–662. doi:10.1161/hc0502.102975