Light the FIRE of revascularization in older patients with myocardial infarction

Comment on ‘Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction’, which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2300468. The Functional Assessment in Elderly MI Patients with Multivessel Disease (FIRE) trial is an investigator-initiated, industry-funded, multicentre, prospective, randomized trial aiming to test the superiority of a strategy of physiology-guided complete myocardial revascularization with percutaneous coronary intervention (PCI) as compared with a culprit-only PCI strategy in older patients with myocardial infarction (MI) and multivessel disease (MVD).1 Older patients (≥75 years of age) admitted with a diagnosis of ST-segment elevation MI (STEMI) or non-STEMI (NSTEMI) and successfully treated with PCI of the culprit lesion, who had MVD and at least one non-culprit coronary lesion with an angiographic diameter stenosis of 50% to 99% in a vessel with a minimum diameter of ≥2.5 mm, were enrolled. Patients with unclear culprit lesion, non-culprit lesion in left main coronary artery, planned or prior surgical revascularization, or life expectancy < 1 year were excluded. Patients were randomized (either immediately or within 48 h from PCI of the culprit lesion) in a 1:1 ratio to physiology-guided complete revascularization or culprit-only revascularization. In the complete revascularization arm, all functionally significant non-culprit lesions, as defined by wire-based or angiography-based measurements, were treated with PCI. The use of sirolimus-eluting, biodegradable polymer, ultrathin stents and dual-antiplatelet therapy for at least 1 year were recommended. The primary endpoint was a composite of all-cause death, MI, stroke, or ischaemia-driven coronary revascularization at 1 year. The key secondary endpoint was a composite of cardiovascular (CV) death or MI at 1 year. The safety endpoint was a composite of contrast-associated acute kidney injury, stroke, or bleeding [defined as type 3, 4, or 5 according to the Bleeding Academic Research Consortium (BARC) criteria] at 1 year. Between July 2019 and October 2021, a total of 1445 patients [median age (interquartile range, IQR), 80 years (77 to 84); 37% female; 35% with STEMI] were enrolled at 34 sites in Italy, Spain, and Poland. In the complete revascularization arm, PCI of at least one non-culprit vessel was performed in 50% of patients. The primary endpoint was significantly less frequent in the complete revascularization group than in the culprit-only group [16% vs. 21%; hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.57 to 0.93; P = .01] with a number needed to treat to prevent the occurrence of one primary-outcome event of 19 patients. The benefit was driven by a reduction in the incidence of each individual component of the primary endpoint, with the exception of stroke. Cardiovascular death or MI was also less frequent in the complete revascularization group than in the culprit-only group (9% vs. 14%; HR, 0.64; 95% CI, 0.47 to 0.88). The incidence of the safety endpoint was not different between the two groups (23% vs. 20%; HR, 1.11; 95% CI, 0.89 to 1.37; P = .37). A substantial proportion of patients presenting with MI (up to 50% of cases) have disease in non-culprit vessels.2 A number of randomized clinical trials (RCTs) demonstrated improved clinical outcomes after complete revascularization with a benefit on CV death and MI.3 Based on this evidence, the recently released European Society of Cardiology (ESC) guidelines for the management of acute coronary syndromes recommend a complete revascularization strategy both for patients with STEMI (class I, level of evidence A) and NSTEMI (class IIa, level of evidence C).4 However, the mean age of patients enrolled in these trials ranged between 62 and 65 years, and older patients (>75 years) were underrepresented. In fact, the management of older patients with MI presents unique challenges variably related to the greater burden of comorbidities, frailty, more complex coronary artery disease, as well as higher risk of procedural complications and side effects of multidrug treatments.2 Another important issue when managing older patients is the competing risk, as the occurrence of death may preclude the observation of a clinical event of interest and the potential benefit associated with an intervention. The FIRE trial fills this important gap in evidence, demonstrating that a strategy based on complete revascularization guided by functional assessment improves the clinical outcome of older patients with MI without apparent safety issues.1 The treatment benefit was largely driven by a reduction in hard clinical outcomes. Of note, patients enrolled in the FIRE were almost 20 years older than those enrolled in previous RCTs and had a higher CV risk profile,3 which might account for the higher-than-expected incidence of events observed in the control arm (21% vs. 15%). The effect size of complete revascularization was consistent with that observed in previous RCTs.3 This suggests that, given the higher background risk, the absolute benefit of such a strategy might be even more relevant in older patients. A major strength of the FIRE is the enrolment of a high proportion of patients with NSTEMI. While there is a large body of evidence about the management of patients presenting with STEMI and MVD,3 a dedicated trial comparing complete revascularization with culprit-only PCI in NSTEMI patients was lacking. Data from previous observational studies suggested that complete revascularization might be associated with lower rates of deaths and hard CV events compared to culprit-only PCI,5 and the causal nature of this association is now strengthened by data from the FIRE trial. Unlike most previous RCTs, complete revascularization was guided by coronary physiological assessment in the FIRE trial. This approach avoided stent implantation in half of non-culprit lesions tested. This is particular relevant in an older population, as the number of implanted stents and treated vessels is a major determinant of dual-antiplatelet therapy duration, which in turn is associated with higher risk of major bleeding and mortality in this high-bleeding risk setting.2 It should be noted, however, that more than 40% of non-culprit lesions were in the angiographic diameter stenosis range of 50% to 69%, meaning that they would have been likely left untreated using an angiography-guided approach. The recent Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction (FLOWER-MI) trial showed no difference in clinical outcomes between physiology-guided and angiography-guided complete revascularization in STEMI patients.6 Yet, whether the findings of FIRE trial can be transferred to an angiography-guided complete revascularization strategy remains undetermined. The functional significance of a non-culprit lesion may be underestimated in the acute setting, in part due to increased microvascular resistance and/or blunted adenosine response (during hyperaemic testing) at the time of MI.7 Of note, in FIRE, all physiology assessments and treatments were performed during the index hospitalization, and mostly in the context of the index procedure. On the other hand, relying solely on angiographic assessment of non-culprit lesions may be misleading, as diffuse coronary vasoconstriction is often present in the acute phase of MI which might affect stenosis assessment.8 Using functional tests to select non-culprit lesions may seem counterintuitive for prediction of CV death or MI, which are typically caused by acute plaque complications and are related to plaque vulnerability. However, there are some data in support of an association between functional significance and plaque vulnerability.9 Additional insight into this issue will be provided by ongoing studies comparing physiology-guided vs. imaging-guided non-culprit lesion revascularization.10 Other interesting questions to address in future analyses are whether the benefits of complete revascularization persist over longer term, and whether this strategy is cost-effective in an older population. In conclusion, the FIRE findings support the complete revascularization strategy in older patients with MI and MVD, highlighting a clear need for broader inclusion and better representation of older patients in RCTs to inform the best practice for this growing population. The personalized care of these more vulnerable patients requires a detailed knowledge of comorbidities, frailty, and cognitive status, as well as the individual patient’s goals of care and quality of life. R.V. received consulting or lecturing fees from Abbott Vascular, Daiichi Sankyo, Amgen, Medtronic, and Terumo, outside the submitted work.