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The ST-segment elevation myocardial infarction (STEMI) patients due to stent thrombosis (ST) remain a therapeutic challenge for a clinician. Till date, very few researches have been conducted regarding the safety and effectiveness of primary percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (DES) for STEMI caused by very late ST (VLST). This retrospective study evaluated the safety, efficacy, and outcomes of primary PCI with second-generation DES for STEMI due to VLST compared with primary PCI for STEMI due to de novo lesion.Between January 2007 and December 2013, STEMI patients with primary PCI in Fuwai Hospital had only second-generation DES implanted for de novo lesion (558 patients) and VLST (50 patients) were included in this retrospective study. The primary end points included cardiac death and reinfarction. The secondary end points included cardiac death, reinfarction, and target lesion revascularization. Continuous variables were expressed as mean (standard deviation) or median (interquartile range) and compared by Student's t-test or Mann-Whitney U-test as appropriate. Categorical variables were expressed as counts and percentages, and comparison of these variables was performed with Chi-square or Fisher's exact test. A two-tailed value of P < 0.05 was considered statistically significant for all comparisons. Statistical analyses were performed by SAS software (version 9.4, SAS Institute Inc., Cary, USA) for Windows.In-hospital primary end point and the secondary end point were no significant differences between two groups (P = 1.000 and P = 1.000, respectively). No significant differences between two groups were observed according to the long-term primary end point and the secondary end point. Kaplan-Meier survival curves showed no significant difference between the two groups in the primary end point and the secondary end point at 2 years (P = 0.340 and P = 0.243, respectively). According to Cox analysis, female, intra-aortic balloon pump support, and postprocedural thrombolysis in myocardial infarction flow 3 were found to be independent predictors for long-term follow-up.Primary PCI with second-generation DES is a reasonable choice for STEMI patients caused by VLST.