BACKGROUNDShenfu injection, as a traditional Chinese medicine, can alleviate reperfusion injury after ST-segment elevation myocardial infarction (STEMI) through multiple pharmacologic effects. This trial aimed to evaluate the effect of Shenfu injection on myocardial injury in STEMI patients undergoing primary percutaneous coronary intervention (PCI).METHODSThis was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. First-time anterior STEMI patients undergoing primary PCI within 12 hours of symptom onset due to a proximal or mid left anterior descending artery occlusion were randomized 1:1 to receive either intravenous Shenfu injection or placebo before reperfusion and followed by once a day until 5 days after primary PCI. The primary endpoint was infarct size by cardiac magnetic resonance (CMR) at 5 days after randomization.RESULTSA total of 295 patients were randomized with evaluable CMR in 273 patients. Infarct size (37.4±14.1% vs 37.5±14.5%; effect size −0.04%, 95% confidence interval: −3.45, 3.37; P=0.982) did not differ between the Shenfu injection and placebo groups. This was true for other CMR parameters. The area under curve for creatine kinase-myocardial band did not differ between groups. The incidences of thrombolysis in myocardial infarction (TIMI) flow grade 3 (94.8% vs 97.1%, P=0.324), TIMI myocardial perfusion grade 3 (91.7% vs 92.1%, P=0.914), and ST-segment resolution ≥70% (25.4% vs 26.1%, P=0.906), were also similar between groups. Adverse events were evenly distributed across groups.CONCLUSIONSFor patients with anterior STEMI undergoing primary PCI, administration of Shenfu injection was safe but did not reduce infarct size by CMR.REGISTRATIONURL:https://www.clinicaltrials.gov; Unique identifier:NCT04493840.Clinical PerspectiveWhat Is New?Among 295 anterior ST-segment elevation myocardial infarction patients randomized to intravenous Shenfu injection or placebo, the primary analysis demonstrated that the infarct size revealed by cardiac magnetic resonance was 37.4 % in the Shenfu injection group and 37.5% in the placebo group, a difference that was not statistically significant.For patients with anterior ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention, administration of Shenfu injection was safe and well tolerated.What Are the Clinical Implications?Cardiovascular clinicians need to realize that successful cardioprotective therapies may require synergistic multitarget approaches.Future clinical trials are required to investigate the use of additive cardioprotective strategies in patients with large infarcts or severe hemodynamic alterations (eg. concomitant heart failure or cardiogenic shock).