Due to a longer life expectancy, the number of people above age 80 years is growing rapidly in Europe and Northern America. Consequently, elderly patients account for an increasing proportion of patients admitted to Intensive Cardiac Care Units (ICCU) with acute coronary syndromes (ACS). Currently about one-third of ICCU admissions are of patients aged $>$75 years [1]. Comorbidities and geriatric syndromes worsen prognosis and make management and risk stratification more complex in these patients [2]. Although there are many risk scoring tools for ACS, it is important to acknowledge that each individual score has limitations and that octogenarians have been under-represented in their development. As age itself is incorporated into most risk score algorithms, elderly patients will be often classified as high-risk based on their age alone.

The oldest patients, and particularly octogenarians, have been excluded from most randomized clinical trials conducted before 2010. The available data in patients with ACS aged $\ge$80 years are derived from registry data and come mainly from studies with in-hospital and one year follow-up. Long-term data are very limited. There is a long way to go to improve risk prediction and management in this subgroup of elderly patients.

Elevated blood glucose and renal function are well established prognostic risk factors in ACS [3, 4, 5, 6]. Their contribution to long term prognosis in octogenarians is less known and with controversial results [7, 8]. Therefore, the aim of our study was to assess long-term prognosis of a contemporary octogenarian population admitted to an ICCU with acute myocardial infarction, and the predictive value of two simple parameters obtained at admission: glucose blood level and estimated glomerular filtration rate (eGFR).

The main findings of our study are:

(1) In this contemporary cohort of octogenarian patients with ACS admitted to an ICCU a high proportion of patients was treated invasively, especially the subgroup with STEMI.

(2) Despite that, nearly half of the patients died within 3.5 years (median follow up 2.2 years) after admission.

(3) An ABG $>$186 mg/dL and eGFR 50 mL/min/1.73 m${}^2$ supported identification of the subgroups with the highest in-hospital and long-term risks.

(4) These variables, when added to a medical history based (Model 1) or an index event based predictive model (Model 2), improved long-term risk prediction of all-cause death.

At present, a universal definition for “elderly” is lacking. Even if biological age may not correspond with chronological age, most now consider “elderly” as those aged $\ge$80 years. In the Western world the proportion of octogenarians is expected to triple by the year 2050 [13]. Life expectancy in Spain continues to increase, and a person who reaches 80 years of age can expect to live an average of 9 additional years in men and 10.9 years in women [14]. To undergo randomized clinical trials in elderly patients with ACS is difficult, due to slow enrolment or high selection bias. In spite of the difficulties, over the last decade solid evidence has been obtained about the clinical benefit of an invasive approach [15]. Despite the lack of randomized studies of primary PCI including distinctively elderly patients, the European Society of Cardiology (ESC) 2017 guidelines state that “there is no upper age limit with respect to reperfusion, especially with primary PCI” [16].

Randomized trials have failed to demonstrate a mortality benefit with an invasive approach in elderly population, probably due to the fact that this invasive strategy is still limited to the lower risk population and less comorbid patients and that only half of the patients undergoing angiography will undergo revascularization, the procedure with a potential impact on mortality [17, 18, 19]. However, consistent mortality reductions have been observed in real-world registries of elderly patients with Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) over the last 20 years, concomitant with an increase in the use of an early invasive approach [20, 21]. Based upon this evidence, the ESC 2020 guidelines for management of ACS without persistent ST-segment elevation recommend to apply for older people the same interventional strategies used for the younger ones, although with a more personalized approach [22].

We have included consecutive octogenarian patients, with a median age of 84 years old, admitted to an ICCU with STEMI and NSTE-ACS. Although NSTEMI is the most frequent clinical presentation of ACS in the elderly, in our study two thirds were STEMI patients, reflecting the fact that our hospital is the reference site for primary PCI for a large population. Index event related variables also exhibited high-risk features. Nearly 50% of patients presented Killip class $>$I and one third with ventricular dysfunction (LVEF 40%). Median GRACE score was 163 points (high risk). Although a comparison between STEMI and NSTEMI patients is beyond the scope of our analysis, included NSTEMI patients probably represent a selected subgroup of patients of higher risk but also with better general health and functional status [23]. The percentage of invasively treated patients was high (84.6%), with a PCI performed in 93.6% of STEMI patients and 64.84% of NSTEMI patients.

Scarce information is available with respect to long-term survival of elderly patients with ACS. Kvakkestad et al. [24] analysed in-hospital mortality and long-term survival in a cohort of STEMI patients according to age. In the subgroup of patients $\ge$80 years (68% treated with PCI) in-hospital mortality and 3-year survival were 13% and 52%, respectively [24]. In our series, including STEMI and NSTEMI patients, with a higher rate of PCI, in-hospital mortality was 11.9% and 3.5-years survival 56%. In a recently published retrospective study of NSTEMI patients aged $\ge$75 years, comparing complete revascularization and culprit revascularization, all-cause mortality with a median follow-up of 45.7 months was 40.4% [25].

On admission to hospital, it is recommended to evaluate glycaemic status in all patients with ACS, regardless of a history of diabetes, and to assess kidney function by eGFR for prognostic reasons and to identify patients at risk of contrast-induced nephropathy [16, 22]. In the present study, we have applied the best cut-off points for all-cause death prediction for admission blood glucose and eGFR and segregated the cohort into 3 groups, according to the presence of both, either or no values beyond the cut-offs, allowing discrimination of the subgroups (group 2 and group 3) of patients with a higher long-term mortality and MACE risk. We have focused on these two biomarkers because, unlike some scores, they can be easily obtained and are linked to diabetes and CKD, two established conditions related to the prognosis and severity of presentation of ACS.

Chronic kidney disease is a common condition in elderly ACS patients. The proportion of patients with CKD is increasing constantly as elderly people are living longer, but also because of an increasing prevalence of hypertension and diabetes mellitus. CKD is associated with adverse outcomes through the entire spectrum of ACS [4, 8, 26, 27]. An advanced age and CKD, frequently associated with comorbidities and geriatric syndromes, are often used as reasons to withhold patients from undergoing angiography and PCI [4, 8, 27], despite evidence of improvement in one year [4] and long-term survival with PCI in NSTEMI patients with CKD [27].

Assessment of renal function in elderly people is debated, the issue being whether the lower eGFR values observed at older ages can be attributed to physiologic aging or is associated with kidney disease and comorbidities. There is not a general agreement about which is the best method to estimate GFR rate at advanced ages. We have decided to use the recommended CKD-EPI formula [9] that has also demonstrated good performance with respect to measured GFR in acute STEMI patients [28]. In our cohort, a lower threshold (eGFR 50 mL/min/m${}^2$) than the value that defines significant kidney disease (eGFR 60 mL/min/m${}^2$) was calculated as the best cut-off point for all-cause death prediction. In one of the first studies that established the impact of renal function on clinical outcomes after PCI, a creatinine clearance 50 mL/min had a higher association with death than any variable except for congestive heart failure on presentation [29]. Morici et al. [4] in the Italian Elderly ACS study with patients aged $\ge$75 years old, selected a 45 mL/min/m${}^2$ threshold. This lower value is in concordance with the threshold of 45 mL/min/m${}^2$ recently proposed to define CKD in patients older than 65 years old [30].

Several studies suggest that the association of a lower eGFR with mortality is weaker with increasing age [7, 26]. In the LONGEVO-SCA registry, including NSTEMI patients aged $\ge$80 years, after adjusting for all potential confounders, this association became non-significant in frail patients [8]. In our study, an eGFR 50 mL/min/1.73 m${}^2$ identified a subgroup of octogenarians with increased long-term all cause death. These high-risk patients need close surveillance after PCI, minimization of contrast dose and deferring of nephrotoxic drug initiation to reduce the risk of contrast-associated acute kidney injury (CA-AKI). In a large series of older adults ($\ge$70 years) who underwent coronary angiography, CA-AKI occurred in 16% of patients even with strict hydration protocols, and was an independent predictor of 3-month mortality [31]. One third of these patients did not return to baseline creatinine values, being the group with the highest mortality. We can speculate that further deterioration of renal function could prevent the clinician from prescribing guideline-adherent medications.

Hyperglycaemia during ACS may reflect stress-induced hyperglycaemia (SIH), worsening glycaemic control among diabetic patients or identify previously undiagnosed diabetes. SIH is considered an acute response of the body to many critical illnesses, including ACS, and many observational studies have documented that hyperglycaemia occurs frequently in this context. The association between blood glucose levels on admission and long-term mortality in patients with ACS has been previously recognised regardless of diabetic status [5, 32]. In patients $>$65 years with acute MI this relationship has also been verified, particularly in those without recognized diabetes [5, 6]. We have selected admission serum glucose concentration because it is easily and routinely assessed. Based on ROC curves, the best cut-off point for the prediction of all-cause death was 186 mg/dL, with good specificity (77%). There are still many questions to solve with respect to the relationship between hyperglycaemia and ACS. It is not clear in the literature which is the best parameter to predict outcomes: admission blood glucose, glucose variability, fasting glucose or maximum blood glucose [33]. Besides, the best cut-off point is not established and it has been suggested that in diabetic patients, a higher value could be more appropriate [6, 34]. New metrics have been proposed, including glycaemic gap and stress hyperglycaemia ratio, which eliminate the influence of chronic glycaemic levels. However, it remains unclear whether SIH is a risk factor contributing directly to the poor clinical outcome or a marker of severity of the disease.

Several limitations to this study should be considered. This is a single centre study that includes patients 80 or more years old with ACS, predominantly STEMI, admitted to an ICCU. The population studied probably excluded patients with poor general health and cognitive status, who would have been treated non-invasively outside the ICCU, especially in the subgroup of NSTEMI patients. It is an observational study and we cannot exclude a selection bias and/or uncontrolled confounders. Data regarding medical treatment on admission and at follow-up are lacking. Glucose and creatinine were measured on admission but we are unaware if the time between symptom onset and sample extraction could improve or worsen the observed results. We have not used validated scales for geriatric syndromes or frailty measurements, although STEMI was the more frequent type of ACS seen in our population (more than two thirds of included patients) and a comprehensive geriatric assessment is very difficult in the STEMI scenario. Because our study was limited to octogenarian patients the results may not apply to younger patients. However, we believe that despite these limitations our study provides interesting data regarding risk stratification and prognosis in this subgroup of patients.

Our study evaluates the predictive value for all-cause death of the combination of ABG and eGFR in octogenarian patients with STEMI and NSTEMI. Long-term mortality was high despite PCI being performed in a significant proportion of patients. A high glycaemia concentration on admission ($>$186 mg/dL) and a low eGFR (50 mL/min/1.73 m${}^2$) identify a subgroup of patients with very high risk and worse outcomes. These biomarkers, when added to clinical models, significantly improved their predictive power.

The scope for further reductions in long-term mortality is likely to be much greater for older than for younger patients with acute myocardial infarction. The variables identified in this study provide more opportunities for risk stratification. Treating non-recognised diabetic patients, prescribing guideline adherent therapies in CKD patients and providing access to cardiac rehabilitation teams, together with the use of other specific instruments for geriatric population such as nurse intervention [35], simplifying treatments, and enhancing care transitions, could help improve outcomes in this population.

ESG, OP and GB—conceived and designed the study; JRL, CS, MFG, KV and ARN—collected data; OP and GB—analysed the data; ESG, OP and GB—wrote the paper; AB revised the manuscript. All authors read and approved the final manuscript.

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee (CEIm65/2008).

We would like to thank all the professionals from the ICCU who take care daily of elderly people with kindness and dedication. Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest.