Discussion
This study investigated the association between GTN use preceding PCI for ACS and the incidence of MACE. The noteworthy findings are as follows: (1) Overall, the GTN group had lower pre-PCI blood pressure and a significantly higher incidence of MACE at 1-year follow-up than the non-GTN group, although peak CK level and LVEF after PCI for ACS were similar in the two groups. In addition to LVEF, chronic kidney disease and Killip classification, GTN use showed an independent association with the incidence of MACE. (2) The GTN group had a significantly higher incidence of MACE than the non-GTN group in elderly patients (age ≥75 years); however, the incidence of MACE did not differ between the GTN and non-GTN groups in non-elderly patients (age <75 years). (3) In both the GTN and non-GTN groups, patients who developed MACE had lower pre-PCI blood pressure than those who did not develop MACE. Moreover, the GTN group showed less pre-PCI systolic blood pressure than the non-GTN group among elderly patients, but we did not find such a difference between the GTN and non-GTN groups in non-elderly patients.
The latest guidelines from the Japanese Circulation Society,6 European Society of Cardiology7 and American College of Cardiology/American Heart Association8 recommend the administration of nitrates in the primary management for ACS, except in cases with contraindications such as marked hypotension, bradycardia and complicated right ventricular infarction. However, as Ekmejian et al recently described,17 these guidelines rely on the results from the GISSI-313 and ISIS-4 study14 conducted more than 30 years ago when the treatment of ACS and the demographics of patients with ACS were significantly different from the current situation. Moreover, the results of these studies did not fully support the strong recommendations for the use of GTN for ACS. The percentage of patients with ACS undergoing primary PCI followed by OMT has increased markedly over the past 30 years, and these multidisciplinary treatments have significantly suppressed the development and progression of heart failure and the recurrence of ischaemic events. Additionally, the recent promotion of timely reperfusion after the onset of ST-elevation myocardial infarction includes shortening the D2B time to less than 90 min.18 19 Our hospital data also indicated that the D2B time was 73 min, meeting the goal stated in the guidelines.6 All of these initiatives help preserve cardiac function after ACS, resulting in that the haemodynamically beneficial effect of GTN in the acute phase, might have become relatively limited and less apparent compared with the era without widespread PCI and OMT.
The concerns regarding the safety of GTN use for ACS might have been relatively increased because the number and proportion of elderly patients with ACS increased, and elderly patients are more prone to hypotension after GTN administration.20 This study also confirmed that the GTN group showed less pre-PCI systolic blood pressure than the non-GTN group among elderly patients. Elderly patients 75 or more years of age account for 30%–40% of all hospitalised patients with ACS, and the incidence of ACS-associated death is also mainly observed in this age group.21–23 Similarly, this study included approximately 40% of patients aged 75 or more years, and the trend of outcomes for the study population as a whole and those in this age group were nearly identical. These findings suggest that the incidence of clinical events occurs mainly in elderly patients, which is similar to previous reports. Hence, optimisation of primary management for elderly patients with ACS is required,24 and the pros and cons of GTN use should be debated and examined separately for elderly and non-elderly patients.
The in-hospital and 1-year mortality among patients with ACS can be effectively estimated and identified by the GRACE score,25 26 which consists of eight items, including age and systolic blood pressure. The results of our study indicated a higher incidence of MACE in the GTN rather than the non-GTN group among elderly patients but not among non-elderly patients. Although this study lacks the GRACE score, poor outcomes in the elderly GTN group might be explained partly by risk elevation owing to the accumulation of older age and less systolic blood pressure. Potential mechanisms by which GTN use influences outcomes in elderly patients might include the pronounced blood pressure-lowering effect of GTN via vasomotor instability specific to the elderly population. A future study on whether the risk stratification score incorporating ‘GTN use before primary PCI’ can be developed in patients with ACS may be required.
This study had several limitations. First, the study was a single-centre cohort. Since the PCI strategy directly influences the incidence of MACE, generalising these single-centre results beyond strategical differences requires multicentre validation. Second, the results do not allow us to simply conclude that GTN use preceding primary PCI causally decreases blood pressure on admission and worsens clinical outcomes. There might be potential undetermined cofounders that influenced the present results; therefore, prospective randomised interventional studies to test the efficacy of GTN on clinical outcomes in ACS patients are warranted. Third, this study failed to show data on the time from the onset of chest symptoms to the use of GTN. Although there was no difference in peak CK elevation or LVEF between the GTN and non-GTN groups, the treatment, including GTN administration itself, might have prolonged the time until primary PCI from symptom onset. Finally, patients with ACS presenting with severe symptoms of chest pain might be more likely to be treated with GTN, suggesting that GTN use may be a marker for more severe ischaemia or more compromised patients. The clinical data regarding coronary severity included in this study (eg, the prevalence of multivessel disease) were compared between the GTN and non-GTN groups, but none showed a clear difference. However, if a more detailed and quantitative coronary severity grading system, such as the SYNTAX score, could have been incorporated into this study, potential confounding factors affecting outcomes in the GTN and non-GTN groups might have been identified.
In conclusion, GTN use preceding primary PCI was associated with adverse clinical outcomes in elderly patients with ACS. Further studies are needed to re-evaluate the impact of GTN use on clinical outcomes in these patients.