Adjunctive Intracoronary Thrombolysis During Primary Percutaneous Coronary Intervention in STEMI

Background: Microvascular obstruction (MVO) remains a major contributor to adverse outcomes following primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). Adjunctive intracoronary thrombolysis was trialed to reduce residual thrombi following primary PCI in STEMI, and initial trials showed benefit. The publication of STRIVE, the largest randomized trial of intracoronary alteplase to date- with a negative result, prompted this updated meta-analysis with fibrin-specificity stratification of agents to determine whether a biological efficacy-gradient exists and whether any agent class confers meaningful clinical benefit. Methods: A meta-analysis of trials in databases searched from inception through February 2026 was performed. Eligible RCTs enrolled STEMI patients undergoing primary PCI randomized to intracoronary thrombolytic versus placebo/standard care. Trials were classified a priori as non-fibrin-specific (streptokinase, urokinase), moderately specific (prourokinase), or highly specific (alteplase, tenecteplase). Subgroup interaction was tested by chi-square test across strata. Results: Sixteen RCTs enrolling 2,598 patients met inclusion criteria. A statistically significant subgroup interaction for composite MACE was identified (χ 2 =8.08, df=2, P=0.018), proving the hypothesized efficacy-specificity gradient. Composite MACE was reduced in the non-fibrin-specific (OR 0.36; 95% CI 0.17-0.79; P=0.010) and moderately fibrin-specific tiers (OR 0.56; 95% CI 0.38-0.81; P=0.002), with no effect in the highly fibrin-specific tier (OR 1.06; 95% CI 0.70-1.61; P=0.77). No individual clinical endpoint (cardiovascular mortality, reinfarction, or heart failure hospitalization) reached statistical significance in any tier, including those where composite MACE was reduced. This dissociation reflects substantial heterogeneity in MACE definitions, obscuring the true efficacy of these agents. TIMI 3 flow and MBG grade 3 significantly favored intracoronary thrombolysis in the moderately fibrin-specific tier (OR 2.46 and 2.36; both P<0.001), with a significant interaction for impaired myocardial perfusion across tiers (χ 2 =14.97, P=0.0006). In the highly fibrin-specific tier, absent MACE benefit was concordant with absent angiographic benefit across all measures. Conclusions: Adjunctive intracoronary thrombolysis confers no individually significant clinical benefit across any fibrin-specificity tier, and composite MACE reductions in less fibrin-specific tiers are not supported by individual endpoints. IC alteplase demonstrates no benefit on any clinical or angiographic measure and should be considered a closed avenue for investigation. Future trials should prioritize moderately fibrin-specific agents and incorporate cardiac MRI endpoints to directly judge microvascular injury.