Impact of preprocedural coronary flow grade on duration of dual antiplatelet therapy in acute myocardial infarction

We investigated the impact of pre-percutaneous coronary intervention (pre-PCI) thrombolysis in myocardial infarction (TIMI) flow grade (pre-TIMI) on 3-month (3-mo) and 12-mo of dual antiplatelet therapy (DAPT) in patients with acute myocardial infarction (AMI). This was a post hoc analysis of the TICO trial. A total of 2083 patients with AMI (pre-TIMI 0/1: n = 1143; pre-TIMI 2/3: n = 940) were evaluated. The primary outcome was the occurrence of net adverse clinical events (NACE), defined as a composite of TIMI major bleeding and major adverse cardiac and cerebrovascular events (MACCE) within 12-mo following PCI. The secondary outcomes were the occurrence of the individual components of TIMI bleedings and MACCE. In the pre-TIMI 0/1 group, the primary and second outcomes were not significantly different between the 3-mo and 12-mo DAPT groups. However, in the pre-TIMI 2/3 group, the occurrences of TIMI minor (adjusted hazard ratio [aHR]: 0.294; p = 0.016) and major or minor bleeding (aHR: 0.483; p = 0.014) on intention-to-treat analysis were significantly higher in the 12-mo than in the 3-mo DAPT group. The occurrence of MACCE was similar between the two groups. A higher bleeding tendency in 12-mo DAPT compared with 3-mo DAPT was more obvious in the pre-TIMI 2/3 group than in the pre-TIMI 0/1 group. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02494895.


ST-segment elevation versus non-ST-segment elevation myocardial infarction (STEMI vs. NSTEMI).
The comparison of clinical outcomes between STEMI and NSTEMI is summarized in Supplementary material 12. After adjustment, in patients with both pre-TIMI 0/1 and 2/3, the occurrence of NACE, TIMI bleedings (major, minor, and major or minor), and MACCE were not significantly different between STEMI and NSTEMI. Supplementary material 13 shows univariate analysis for NACE according to the pre-TIMI in comparing STEMI and NSTEMI.
Interaction between pre-TIMI during an index PCI and the duration of DAPT. Table 4 shows the interaction between pre-TIMI during an index PCI (pre-TIMI 0/1 vs. 2/3) and the duration of DAPT (3-mo or 12-mo DAPT). There were no significant interactions between the different pre-PCI TIMI during an index PCI and the duration of DAPT after adjustment.

Discussion
The TIMI flow grade is a traditional method for assessing coronary blood flow 11 . Previous studies have shown that various pro-thrombotic markers including platelet count, reactivity, and mean platelet volume were associated with patency of the infarct-related artery in patients with STEMI, before primary PCI 12,13 . Moreover, in the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) and HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) Trials, pre-TIMI 3 was an important independent predictor of 1-year survival 14 . The main findings of this study were as follows: (1) in patients with pre-TIMI 0/1, the occurrence of NACE, TIMI bleedings (major, minor, and major or minor), and MACCE (all-cause death, cardiac death, MI, ST, and stroke) were not significantly different between the 3-mo and 12-mo DAPT groups. (2) In patients with pre-TIMI 2/3, the occurrence of TIMI minor bleeding and major or minor bleeding were significantly higher in the 12-mo DAPT group than in the 3-mo DAPT group. Moreover, on 3-mo landmark analyses between 3-mo and 12-mo, the occurrence of TIMI major bleeding was significantly higher in the 12-mo DAPT group than in the 3-mo DAPT group. However, the occurrence of MACCE was similar between the 3-mo and 12-mo DAPT groups. (3) The occurrence of NACE, TIMI bleeding, and MACCE were not significantly different between STEMI and NSTEMI. The present data indicate that pre-TIMI 0/1 is present in 54.8% (STEMI, 68.5%, vs. NSTEMI, 31.5%) and pre-TIMI 2/3 is present in 45.2% (STEMI, 31.1%, vs. NSTEMI, 68.9%). The ratio STEMI/NSTEMI is at the complete opposite between the pre-TIMI 0/1 and 2/3 groups. However, these results are comparable with Bailleul et al. www.nature.com/scientificreports/ study 15 . Although the proportions of STEMI and NSTEMI in patients with pre-TIMI 0/1 or 2/3 were different, these proportions were not significantly different between the 3-mo DAPT or 12-mo DAPT groups (Table 1). Especially, in Table 3, STEMI was included in the multivariate analysis as a significant variable with other variables. The occurrence of TIMI major or minor bleeding was significantly in the pre-TIMI 2/3 group than in the pre-TIMI 0/1 group, similar to the results in Table 2. In addition, as shown in Supplementary material 10, in patients with both pre-TIMI 0/1 and 2/3, the occurrence of NACE, TIMI bleeding (major, minor, and major or minor), and MACCE were similar between STEMI and NSTEMI. A ruptured, eroded, or protruding calcified atherosclerotic plaque could trigger local thrombosis, which is a critical step in the pathogenesis of AMI 16 . To date, it remains unclear why some plaques lead to STEMI with poor pre-TIMI but others do not 17 . Compared to pre-TIMI 0/1, which has prolonged ischemia and late reperfusion, can impair endothelial function, and cause myocardial tissue edema, pre-TIMI 2/3 would have shorter ischemic time and less myocardial damage 17 . In a state of endothelial dysfunction, disruption of the balance between anti-thrombosis and pro-thrombosis can lead to increased platelet aggregation 18 . More recently, Bauer et al. 19 reported that, after adjustment, definite stent thrombosis (ST) occurred only in patients with pre-TIMI 0/1 in their ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation www.nature.com/scientificreports/ Myocardial Infarction to Open the Coronary Artery) sub-study. Moreover, they showed that prehospital administration of ticagrelor was less effective in patients with pre-TIMI 0/1 than those with pre-TIMI 2/3 (0.3% vs. 1.3%, p < 0.05). Hence, it could be assumed that on treatment with 3-mo or 12-mo DAPT, the major clinical outcomes could be influenced by pre-TIMI. However, the effect of pre-TIMI on bleeding and cardiovascular events after ticagrelor-based 3-mo or 12-mo DAPT in patients with AMI has not been reported. Thus, this paper may be considered as the first report focused on this perspective. In our study, compared to the patients with pre-TIMI 0/1, the occurrences of TIMI minor bleeding and major or minor bleeding were significantly higher in the 12-mo DAPT group than in the 3-mo DAPT group, in patients with pre-TIMI 2/3. In addition, on 3-mo landmark analyses between 3-mo and 12-mo, the occurrence of NACE and TIMI major, minor, and major and minor bleeding were also higher in the 12-mo DAPT group than in the 3-mo DAPT group. Because of the absence of previous reports, it could be difficult to provide comparative results between our and previous reports. However, based on our results, it could be considered that the beneficial effects of 3-mo DAPT over 12-mo DAPT in reducing bleeding events are mainly determined by pre-TIMI 2/3 rather than by pre-TIMI 0/1. However, in patients with 12-mo DAPT, the mean age, the number Table 3. Clinical outcomes between pre-PCI TIMI 0/1 and 2/3 groups according to 3-month or 12-month DAPT strategies. Pre-PCI pre-percutaneous coronary intervention, TIMI Thrombolysis In Myocardial Infarction, DAPT dual antiplatelet therapy, HR hazard ratio, CI confidence interval, NACE net adverse clinical events, MACCE major adverse cardiac and cerebrovascular events, MI myocardial infarction, TVR target vessel revascularization, ST stent thrombosis, LVEF left ventricular ejection fraction, STEMI ST-segment elevation myocardial infarction, LM left main coronary artery, ACE angiotensin converting enzyme, CCB calcium channel blocker. a Adjusted by age, LVEF, diabetes mellitus, white blood cell, hemoglobin, STEMI, LM, and single-vessel disease (Supplementary material 16) www.nature.com/scientificreports/ of hypertensive and diabetic patients, and patients with prior history of PCI were significantly higher in the pre-TIMI 2/3 group than in the pre-TIMI 0/1 group. In this study, to adjust the diverse variables, multivariate analysis was performed. But, it could be speculated that these baseline characteristics may play an important role in explaining this higher TIMI major or minor bleeding. Despite the possible benefit of DAPT in reducing ischemic events of infarction, it may be considered that no compound can enter an ischemic no-flow area of myocardium, especially if the culprit coronary artery in totally occlude 7 . Hence, in patients with pre-TIMI 0/1, the occurrence of NACE, TIMI bleeding, and MACCE would not be significantly different between the 3-mo or 12-mo DAPT groups. In contrast, patients with pre-TIMI 2/3 treated with 12-mo DAPT showed a higher incidence of bleeding tendency than those with 3-mo DAPT without showing increased incidences of ischemic events. According to the subgroup analysis (Figs. 2 and 3), in both pre-TIMI 0/1 and 2/3, and in patients with single-vessel disease, 3-mo DAPT may be preferred over 12-mo DAPT to reduce NACE in this study.
In the FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial infarction) study, after 2010, there was no further mortality gain was founded in patients with STEMI with reperfusion therapy or in patients with NSTEMI, regardless of performing PCI 20 . Moreover, there are some debates regarding the long-term prognosis between STEMI and NSTEMI [21][22][23] , the occurrence of NACE, TIMI bleeding, and MACCE were not significantly different between these two groups both in pre-TIMI 0/1 and 2/3 groups (Supplementary material 12) in our study and our results were consistent with those of Montalescot's findings 23 .
Based on our results, considering pre-TIMI may be helpful to understand more accurately the comparative outcomes between short and standard 12-mo DAPT in patients with AMI receiving new-generation DES.
This study has some limitations. First, although the TICO trial was an open-label trial, this trial was not a placebo-controlled study. Therefore, drug adherence was not monitored. Second, the lower-than-expected rate of adverse events in the main TICO trial could be a limitation in this study. Therefore, caution regarding the interpretation of our study results is needed. Third, because the ultrathin bioresorbable polymer sirolimulseluting stent (Orsiro; BIOTRONIK, Buelach, Switzerland) was deployed in the whole study population in this study, diverse results that would reflect many other kinds of new-generation DES that are currently in use were not included in this study. Fourth, because platelet function tests (e.g., P2Y 12 reaction unit) and aspirin reaction unit, mean platelet volume, and myocardial blush grade were not monitored before, during, and after PCI in the TICO trial, we could not provide this information. Fifth, because the use of intravascular ultrasound, optical coherence tomography, and fractional flow reserve (FFR) were not mandatory tools for treatment in the main TICO trial, we could not provide results according to the use of these imaging and functional testing tools for the lesions. Finally, even if pre-TIMI is easy and inexpensive, it could be a suboptimal, incomplete measure of myocardial perfusion. Moreover, although the TIMI flow grade is often used to evaluate blood flow during acute coronary occlusion and/or reperfusion, as a more instructional reference and more relevant indicators, such as FFR, should be considered to give a more accurate evaluation. Table 4. Interaction between pre-PCI TIMI during an index PCI (pre-PCI TIMI 0/1 vs. 2/3) and the duration of DAPT (3-mo DAPT vs. 12-mo DAPT) for clinical outcomes. a Adjusted for variables that showed differences with p < 0.05 (age, male, LVEF, hypertension, diabetes mellitus, prior MI, prior PCI, serum creatinine, eGFR, STEMI, beta-blocker, CCB, and stent diameter) (Supplementary material 15) between the pre-PCI TIMI 0/1 and pre-PCI 2/3 groups. Pre-PCI pre-percutaneous coronary intervention, TIMI Thrombolysis In Myocardial Infarction, DAPT dual antiplatelet therapy, 3-mo 3-month, 12-mo 12-month, NACE net adverse clinical events, MACCE major adverse cardiac and cerebrovascular events, MI myocardial infarction, TVR target vessel revascularization, ST stent thrombosis, LVEF left ventricular ejection fraction, eGFR estimated glomerular filtration rate, STEMI ST-segment elevation myocardial infarction, CCB calcium channel blocker.

Outcomes
Interaction p value (Intention-to-treat) www.nature.com/scientificreports/ www.nature.com/scientificreports/ In conclusion, our results suggest that the higher bleeding tendency in 12-mo DAPT compared with 3-mo DAPT was more obvious in patients with pre-TIMI 2/3 than in those with pre-TIMI 0/1. However, more studies are warranted to confirm these results.
PCI procedure and medical treatment. Diagnostic coronary angiography and PCI were performed using standard techniques 25 . If the patient was not taking aspirin or ticagrelor at the time of PCI, a loading dose of aspirin (300 mg) and ticagrelor (180 mg) were administered before PCI. Thereafter, 100 mg of aspirin per day and 90 mg of ticagrelor twice per day were prescribed as daily maintenance therapy 4 . After 3-mo DAPT consisting of aspirin and ticagrelor, aspirin was discontinued in the ticagrelor monotherapy group and continued in the 12-mo DAPT group 4 .   4 . In case of NSTEMI, culprit vessel was evaluated by coronary angiographic findings, 12-lead electrocardiogram, two-dimensional echocardiogram, and noninvasive stress test 27,28 . A successful PCI was defined as a residual stenosis of < 30% and TIMI flow grade 3 for the infarct-related artery after the procedure. All baseline and procedural angiographic images including TIMI flow grade of the enrolled patients were centrally collected, and quantitative and qualitative analyses were independently performed in the central angiographic core laboratory (Cardiovascular Research Institute, Severance Cardiovascular Hospital, Seoul, South Korea). Moreover, the PRECISE-DAPT (Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy) score was assessed using an online calculator (http:// www. preci sedap tscore. com) with 5 variables (age, creatine clearance, hemoglobin, white blood cell count, and previous spontaneous bleeding) 29 . Adverse events were centrally collected, and any document that could lead to unblinding of treatment assignment was obliterated before submission to the clinical event committee. Outcomes were categorized according to predefined criteria by an independent clinical event committee blinded to the treatment assignments and primary results of the trial 4 .
Statistical analysis. Primary analyses of this study were performed in an intention-to-treat manner. Prespecified 3-month landmark analyses were performed. Post-hoc analyses were performed for the as-treated population regarding the actual treatments received. Categorical data were reported as numbers and percentages, and they were compared using the chi-square test or Fisher's exact test, as appropriate. Continuous variables were expressed as mean ± standard deviation, and were compared using the Student's t-test. Various clinical outcomes were estimated using the Kaplan-Meier method, and intergroup differences were compared using the log-rank test. To determine meaningful variables, all variables with p < 0.1 and known conventional risk factors for poor outcomes in the AMI population were considered potential confounding factors and were included in the univariate analysis (Supplementary materials 15 and 16). Variables with p < 0.05 were included in the mul- www.nature.com/scientificreports/ tivariate analysis model. For all analyses, a two-sided p value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software version 20 (IBM, Armonk, NY, USA).