Weekly Journal Scan: Do older patients with non-ST-segment elevation myocardial infarction receive any benefit from a routine invasive strategy?

Comment on the article ‘Invasive treatment strategy for older patients with myocardial infarction’ presented at ESC Congress 2024 in London and simultaneously published in The New England Journal of Medicine; https://doi.org/10.1056/NEJMoa2407791. SENIOR-RITA (Older Patients with Non–ST-Segment Elevation Myocardial Infarction Randomized Interventional Treatment) was a multicentre, open-label, randomized trial conducted at 48 sites in the UK and funded by the British Heart Foundation, designed to evaluate the potential beneficial effects of a routine invasive approach as compared with a conservative approach in a population of older patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI). Patients 75 years of age or older with NSTEMI were randomized 1:1 to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization in addition to best available medical therapy. The primary outcome was a composite of death from cardiovascular causes or non-fatal MI assessed in a time-to-event analysis.1 Out of 6977 eligible patients who underwent screening from November 2016 through March 2023, 1518 patients (mean age 82 years; ∼70% ≥ 80 years; 45% women; 68% with ischaemic electrocardiographic changes) were included and randomly assigned to the invasive strategy or to the conservative strategy at a median of 2 days from hospitalization. One-third of enrolled patients were classified as frail according to the Fried Frailty Index; more than 60% had some degree of cognitive impairment according to the Montreal Cognitive Assessment (MoCA) score; the median score on the Charlson Comorbidity Index was 5 (range, 0–37, with higher scores indicating a greater burden of coexisting conditions). Guideline-recommended pharmacotherapy for the management of NSTEMI was well balanced in the two groups, including dual antiplatelet therapy (consisting of aspirin 75 mg daily and clopidogrel or ticagrelor) in 83%, lipid-lowering therapy in 90%, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. In the invasive strategy group, 90% underwent coronary angiography and 50% revascularization within 3–7 days from admission (median 5 days), mainly by percutaneous coronary intervention (PCI; performed in 47%) via the radial artery access, at the discretion of the attending cardiologist and the multidisciplinary team [multivessel PCI was performed in 30%, and coronary-artery bypass grafting (CABG) in 3% of cases]. Interestingly, patients who did not undergo randomization had similar clinical and demographic characteristics to patients who had undergone randomization. In the conservative-therapy group, coronary angiography was allowed if the patient had clinical deterioration, and the procedure was clinically indicated (n = 43 patients). The median follow-up was 4.1 years. There was no difference in the primary endpoint of cardiovascular death or non-fatal MI between the invasive strategy group (25.6%) and the conservative strategy group (26.3%) [hazard ratio (HR) 0.94; 95% confidence interval (CI) 0.77–1.14; P = .53]. This was consistent across all pre-specified subgroups. Cardiovascular death occurred in 15.8% of the invasive strategy group vs. 14.2% of the conservative strategy group (HR 1.11; 95% CI 0.86–1.44). There were numerically fewer non-fatal MIs (11.7% vs. 15.0%; HR 0.75; 95% CI 0.57–0.99), and subsequent revascularization procedures (3.9% vs. 13.7%; HR 0.26; 95% CI 0.17–0.39) in the invasive strategy group. However, because there was no adjustment for multiplicity, the widths of the confidence intervals should not be interpreted as reflecting treatment effect. There were no differences in the other secondary outcomes, including all-cause death, fatal and non-fatal MI, stroke, and hospitalization for heart failure. However, transient ischaemic attacks (2.4% vs. 1.2%) and bleeding events (8.2% vs. 6.4%) were numerically higher in the invasive strategy group. The rate of procedural complications was <1%. In higher-risk patients with NSTEMI, current guidelines for the management of acute coronary syndromes (ACS) recommend an invasive strategy over medical therapy alone.2,3 Guidelines also include specific recommendations for the elderly, who now represent an increasing proportion of ACS patients, emphasizing that the same diagnostic and treatment strategies should be applied to both older and younger adults with ACS, while carefully assessing the risks and benefits of different treatment approaches.2,3 However, older NSTEMI patients are less likely to receive guideline-recommended care, including the use of an invasive strategy.4 This may be due to several factors. Older patients are often underrepresented in clinical trials evaluating NSTEMI treatment strategies, leading to a lack of robust, evidence-based recommendations for their care.5 This evidence gap, combined with clinician or patient concerns about procedural risks or potential futility, often leads to a more conservative approach. SENIOR-RITA is the largest randomized controlled trial (RCT) to date evaluating an invasive strategy in a representative group of older NSTEMI patients, including those who are frail, cognitively impaired, or have multiple conditions, making its findings applicable to unselected elderly populations.1 The trial shows that, contrary to a common belief, coronary revascularization in elderly patients using a radial artery access is relatively safe. However, an invasive strategy did not result in a lower risk of a composite of cardiovascular death or non-fatal MI than a conservative strategy, over a relatively long follow-up. Six previous RCTs examined the potential benefits of an invasive treatment strategy in older NSTEMI patients, but these studies had major limitations such as small sample sizes (106–457 patients), lack of formal frailty or cognitive assessments, and no adjudication of events.6–11 A patient-level meta-analysis of these trials including 1479 patients found that routine invasive treatment, compared to conservative management, did not reduce the risk of a composite outcome of death from any cause or MI within one year. However, the invasive strategy was associated with lower risks of MI and urgent revascularization.12 The main finding of SENIOR-RITA appears consistent with this meta-analysis, in terms of their primary composite outcomes, despite a four-fold longer duration of follow-up. However, there remains statistical uncertainty concerning the secondary endpoints of non-fatal MI and fatal or non-fatal MI. SENIOR-RITA has several limitations, including fewer primary outcome events than expected, thereby reducing the statistical power of the study to <80%. The authors highlighted challenges in recruiting older adults for clinical research, especially frail patients with multiple conditions, and noted the impact of the COVID-19 pandemic on recruitment. While the SENIOR-RITA population is broadly representative, the results may not apply to all elderly NSTEMI patients. The average GRACE (Global Registry of Acute Coronary Events) risk score was 135, leaving uncertainty about outcomes for those with higher scores. Additionally, the study primarily focuses on PCI, so the findings may not extend to patients requiring CABG. More data on the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score and disease complexity would help clarify these aspects. The timing of revascularization is also relevant, with patients in the invasive arm undergoing PCI a median of 5 days after NSTEMI admission, which may have influenced the outcomes. The importance of complete revascularization needs also to be emphasized. In SENIOR-RITA, only 28% of patients with multivessel disease received multivessel PCI (the remaining receiving single vessel PCI or no revascularization). The FIRE trial, which involved a similar elderly population (mean age, 82 years), showed that physiology-guided complete revascularization in elderly patients with ST-segment elevation MI (STEMI) and NSTEMI was associated with a lower risk of death, MI, stroke, or ischaemia-driven revascularization at 1 year compared to culprit-lesion-only PCI.13 The SENIOR-RITA trial included a higher percentage of patients with frailty (32% vs. 10%) and cognitive impairment (60% vs. <10%), with a lower average GRACE score (135 vs. 180), indicating different patient characteristics and risks. Whether complete revascularization could improve outcomes compared to a more conservative strategy remains to be established in this setting. While frailty and cognitive impairment are important considerations, factors such as left ventricular dysfunction, SYNTAX score, and the completeness of revascularization likely drive non-fatal events and death. These factors may help explain the apparent discrepancy between a numerical reduction in non-fatal MI and no impact on cardiovascular death in the SENIOR-RITA trial. Finally, in an elderly population, longevity may not be the primary goal; freedom from stroke and rehospitalization might be more important, though the invasive strategy did not reduce stroke or rehospitalization in the current trial. Despite its limitations, the trial provides valuable medium-term insights into patient care and strengthens the evidence base, enabling patient-centred discussions and more informed decisions. SENIOR-RITA also highlights the importance of ensuring that older patients are adequately represented in future clinical trials of ACS management strategies. In conclusion, neither the meta-analysis of six previous trials nor the SENIOR-RITA trial validated the hypothesis of a substantial benefit of a routine invasive strategy on fatal and non-fatal vascular outcomes in elderly patients with NSTEMI, regardless of their baseline characteristics and concurrent conditions. The limited statistical power of these analyses may be responsible for the apparent treatment failure that may well mask a smaller effect size than expected. G.L. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis; G.L. reports grant support (to the Institution) for investigator-initiated research from the American Heart Association, the Italian Ministry of University and Research, and the Italian Ministry of Health (Grant: ‘Ricerca Corrente’). C.P. reports personal fees from AbbVie, Eli Lilly, and Tremeau, and past grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.

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