Management of acute coronary syndromes in older adults

Abstract

Older patients are underrepresented in prospective studies and randomized clinical trials of acute coronary syndromes (ACS). Over the last decade, a few specific trials have been conducted in this population, allowing more evidence-based management. Older adults are a heterogeneous, complex, and high-risk group whose management requires a multidimensional clinical approach beyond coronary anatomic variables. This review focuses on available data informing evidence-based interventional and pharmacological approaches for older adults with ACS, including guideline-directed management. Overall, an invasive approach appears to demonstrate a better benefit–risk ratio compared to a conservative one across the ACS spectrum, even considering patients’ clinical complexity and multiple comorbidities. Conversely, more powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and no benefit in terms of mortality reduction. An interdisciplinary evaluation with geriatric assessment should always be considered to achieve a holistic approach and optimize any treatment on the basis of the underlying biological vulnerability.

Graphical Abstract

Older patients and acute coronary syndrome: assessment and management.

Older adults, acute coronary syndrome, elderly, frailty

Introduction

Ageing is a progressive condition without a universally accepted age threshold to define ‘older adults’, though in cardiovascular (CV) treatment studies a cut-off of 75 years is the most recurrent.¹ Older adults currently account for 6% of the population worldwide, and by the year 2050, the predicted proportion in Western countries is expected to reach 11.5%, with octogenarians growing even faster than the number of older persons overall.²

Ageing fosters an increased CV burden, being heart disease more common in older adults. CV ageing is the result of key structural and functional changes at cellular and subcellular levels that impact the entire vascular system, including large and small arteries, altering systolic and diastolic myocardial function and sensitivity to sympathetic stimuli, finally promoting CV diseases (Figure 1).³ Two-third of all patients with CV disease are >60 years of age, and >85% of octogenarians live with some forms of CV disease.⁴,⁵ According to intensive cardiac care unit (ICCU) registries, individuals aged ≥75 years represent about 30% of patients with ST-elevation myocardial infarction (STEMI) and 40% of those with non-ST-elevation myocardial infarction (NSTEMI).^6–8 These figures likely underestimate the actual number of hospital admissions with acute coronary syndromes (ACS) since up to 17% of the older patients with myocardial infarction (MI) are admitted in non-specialized wards.⁹

Figure 1

Changes in pathophysiological pathways in older adults.

The evidence guiding treatment strategies in older ACS patients was modest before 2010 since most randomized clinical trials (RCTs) had included only younger populations.^{10  ,  11} Observations coming from national ACS surveillance systems across the world have consistently shown that older adults are less likely to receive guideline-recommended therapies compared to younger patients.^12–14 This may likely result from atypical symptoms leading to high rates of late presenters, and physicians’ awareness that the benefit of a more intensive treatment, including any stay in ICCU, is counterbalanced by increased bleeding risk, diminished quality of life, as well as functional and cognitive decline.^15–18

Specific prospective trials in older adults have been carried out over the last decade, comparing medical and interventional treatment in the acute phase and antithrombotic strategies within one year after an ACS (Table 1). Temporal trends over a period of 15 years have shown a growing use of revascularization in the acute phase and a positive association of this approach with improved outcome.^{6  ,  31} On the other hand, guideline recommendations on post-acute drug therapy, particularly antiplatelet therapy, have been built upon the evidence from RCTs whose populations had a mean age of 60–65 years.^32–34 The care of older adults in ACS is complicated by the increased atherothrombotic and thromboembolic risks, but also bleeding risk, compared to younger patients,^35–38 and by the complexity of geriatric syndrome, which involves frailty, multimorbidity and polypharmacy.³⁹ Therefore, as discussed in the present review, the care for older adults with ACS should be tailored on an individual basis, carefully considering the risk vs. benefit of an invasive approach, compared to a conservative one, and of the strategies of antithrombotic therapy for secondary prevention (Graphical abstract).

Table 1

Prospective studies in older adults with Acute Coronary Syndrome published over the last decade

Study	N  b of patients	Year of publication	Population, mean age, % women	Methodology	Aim of the study	Main results
TRIANA19	266	2011	STEMI, 81 years, 44% women	RCT	Primary PCI vs. lytic therapy in STEMI patients ≥75 years	No significant benefit with primary PCI vs. thrombolysis [OR 0.69 (95% CI 0.38–1.23)] for the composite of all-cause death, Re-infarction and stroke at 30 days.
Italian Elderly ACS20	313	2012	NSTE-ACS, 82 years, 50% women	RCT	Early invasive vs. initially conservative approach in NSTE-ACS ≥75 years	No difference in 1-year MACEa for the overall population [HR 0.80 (0.53–1.19)]. Significant benefit with early invasive approach only in troponin positive patients [HR 0.43 (0.23–0.80)].
After Eighty21	457	2016	NSTE-ACS, 85 years, 50% women	RCT	Early invasive vs. initially conservative approach in NSTE-ACS ≥80 years	Significant benefit of an early invasive approach [HR 0.53 (0.41–0.69)] on the composite of MI, death, stroke and urgent revascularization (median follow-up 1.53 years).
ANTARCTIC22	877	2016	All ACS, 81 years, 40% women	RCT	Effect of platelet function monitoring and P2Y12 treatment adjustment after stenting in ACS patients aged ≥75 years	No benefit of platelet function monitoring [HR 1.003 (0.78–1.29)] on the 1-year composite endpointb
LADIES ACS23	675	2016	All ACS, 74 years, 63% women	Prospective observational	Age and sex-matched angiographic assessment and 1-year outcome in four decades of age classes from >55 to >85 years	Women show lower Gensini score than men at any age (P < 0.001). Menopausal age was not associated with the extent of coronary artery disease (R = 0.063, P = 0.228)
Elderly ACS 224	1443	2018	All ACS, 80 years, 40% women	RCT	A comparison of prasugrel 5 mg and clopidogrel 75 mg after stenting in ACS patients aged ≥75 years	No difference in the primary endpoint of mortality, myocardial infarction, disabling stroke, and rehospitalization for cardiovascular causes or bleeding within 1 year [HR 1.007 (0.78–1.30)]
DEAR-OLD25	696	2018	NSTE-ACS Not yet reported	RCT	Routinely deferred vs. early invasive strategy in patients ≥75 years	Ongoing
SENIOR26	1200	2018	Stable CAD (54%) and ACS (47%), 81 years, 38% women	RCT	DES vs. BMS in patients ≥75 years with short DAPT duration	DES reduced MACCEc at 1 year [RR 0.71 (0.52–0.94)]
POPular AGE27	1002	2020	NSTE-ACS, 77 years, 36% women	RCT	Clopidogrel vs. ticagrelor in NSTE-ACS ≥70 years	Clopidogrel leads to fewer [HR 0.71 (0.54–0.94)] bleeding events (primary endpoint) without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke and bleeding (co-primary endpoint) at 1 year.
SENIOR-NSTEMI28	1976	2020	NSTE-ACS, 86 years, 55% women	Prospective observational	Early invasive vs. initially conservative approach in NSTE-ACS ≥80 years	Early invasive strategy associated with lower cumulative 5-year mortality [adjusted HR 0.68 (0.55–0.84)].
RINCAL29	250	2021	NSTE-ACS, 85 years, 48% women	RCT	Early invasive vs. initially conservative approach in NSTE-ACS ≥80 years	No difference in the composite endpoint of all-cause mortality and re-infarction at 1-year follow-up [HR 0.79 (0.45–1.35)].
SENIOR-RITA30	2300	Ongoing	NSTE-ACS ongoing	RCT	Early invasive vs. initially conservative approach in NSTE-ACS ≥75 years	Ongoing

ACS, acute coronary syndrome; BMS, bare metal stent; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; HR, hazard ratio; CI, confidence interval; MACCE, major adverse cardiac and cerebrovascular events; NSTE-ACS, non-ST-elevation acute coronary syndrome; OR, odds ratio; PCI, percutaneous coronary intervention; R, correlation coefficient; RCT, randomized clinical trial; RR, relative risk.

a

Defined as composite of death, myocardial infarction, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding.

b

A composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, urgent revascularization, and Bleeding Academic Research Consortium-defined bleeding complications (types 2, 3, or 5) at 12-month follow-up.

c

A composite of all-cause mortality, myocardial infarction, stroke, or ischaemia-driven target lesion revascularization.

Risk vs. benefit of a pharmaco-invasive approach

Cardiovascular ageing, characterized by endothelial dysfunction and dysregulated inflammation,⁴⁰ increases the risk of thrombotic events. On the other hand, advanced age is an important risk factor for bleeding. A consensus document recently released from the Bleeding Academic Research Consortium (BARC) has considered age >75 years as a minor high bleeding risk criterion in patients undergoing percutaneous coronary intervention (PCI),⁴¹ with an expected BARC 3 or 5 bleeding rate <4% at 1 year.⁴² However, recent validation studies of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria found that advanced age conferred a BARC 3 or 5 bleeding risk exceeding 4% at the upper limit of the 95% confidence intervals (CI), and suggested that advanced age should rather be a major than a minor criterion.^43–45 Importantly, the risk of bleeding seems to increase linearly with age.⁴⁶

Evidence in patients with ST-elevation myocardial infarction

When fibrinolysis was the universal therapeutic approach for STEMI, older adults were at higher risk of severe bleeding complications, particularly intracranial haemorrhage, with any type of lytic regimen,^47–50 a fact that resulted in lower likelihood of receiving reperfusion therapies.^{51  ,  52}

Primary PCI (pPCI) is particularly attractive in older adults. The first dedicated trial that randomly assigned 87 STEMI patients aged ≥75 years to treatment with either pPCI or intravenous streptokinase showed a significant reduction of the composite of death, re-infarction or stroke at 30 days in the pPCI group as compared to the streptokinase group [relative risk (RR) 4.3, 95% CI 1.2–20.0; P = 0.01].⁵³ In the TRIANA (TRatamiento del Infarto Agudo de miocardio eN Ancianos) multicentre trial, prematurely stopped due to slow recruitment, early presenter (<6 h) STEMI patients (mean age 81 years) randomized to pPCI had a numerically lower rate of the primary endpoint (all-cause death, recurrent MI or disabling stroke at 30 days) than those randomized to fibrinolysis [odds ratio (OR) 0.69, 95% CI 0.38–1.23; P = 0.21], with a significant reduction recurrent ischaemia (0.8% vs. 9.7%, P < 0.001).¹⁹ A pooled analysis of the Zwolle, SENIOR PAMI, and TRIANA trials showed an advantage of pPCI over fibrinolysis in reducing death, recurrent MI, or stroke at 30 days (OR 0.64, 95% CI 0.45–0.91).¹⁹

Registry data covering the time period between 2000 and 2015 (Table 2) showed a progressive increase of pPCI in older adults mirrored by a reduction in lytic therapy and no reperfusion.^{7  ,  54–66} In a retrospective analysis of the National Inpatient Sample database, the largest publicly available all-payer inpatient care database in the USA, 11% of STEMI patients aged ≥70 years underwent PCI in 1998 compared with 35.7% in 2013 with an upward trend of 1.3%/year in the PCI performed and a corresponding downward in the in-hospital mortality rate (P < 0.001).⁶⁷ In a pooled analysis of four French registries, conducted from 1995 to 2010, including 3389 patients aged ≥75 years, early mortality after hospital admission decreased from 25.0% to 8.4%. This improvement was explained by increasing use of early PCI and recommended pharmacological therapies.⁶⁸ Similar trends were observed in Italy between 2001 and 2014 with a reduction in mortality from 18% to 7% in men and from 23% to 11% in women.⁷ Based on this evidence, the European Society of Cardiology (ESC) 2017 STEMI guidelines state that ‘there is no upper age limit with respect to reperfusion, especially with pPCI’.⁶⁹ However, concerns about high prevalence of comorbidities still remain associated with lower rates of coronary catheterization and PCI in older adults.^{6  ,  70}

Table 2

Major registries comparing rates of pPCI and early mortality in elderly vs. younger patients with STEMI

Registry	Enrolment period	Definition of elderly patients	No. of elderly patients	Rates of pPCI in elderly vs. younger pts	Mortality in elderly vs. younger pts
Malaysian National Cardiovascular Disease Database-Acute Coronary Syndrome (NCVD-ACS) registry (16 hospitals in Malaysia)54	2005–2010	≥65 years	1564	16.2% vs. 20.3%; P < 0.001	In-H: 15.9% vs. 5.5%;   P < 0.001
Singapore Myocardial Infarction Registry (all public and private hospitals in Singapore)55	2007–2014	≥65 years	4751	51.0% vs. 74.7%; P < 0.001	30-day: 23.8% vs. 5.7%; P < 0.001
Fattouma Bourguiba University Hospital (Monastir, Tunisia)56	1998–2013	≥75 years	211	24.2% vs. 28.8%;   P = 0.17	In-H: 14.5% vs. 8.1%;   P < 0.005
5 Italian registries6	2001–2014	≥75 years	3733	72.0% vs. 87.0%   P < 0.01	In-H: 11.6% vs. 1.2%   P < 0.001
Minimum Basic Data Set (MBDS) of the Spanish National Health System (all public hospitals in Spain)57	2004–2013	≥75 years	107 890	27.9% vs. 50.0%; P < 0.001	In-H: 9.7% vs. 4.6%;   P < 0.01
7 Arabian Gulf registries58	2005–2017	≥75 years	823	15.4% vs. 21.5%; P = 0.01	In-H: 16.5% vs. 5.1%; P < 0.001
EUROTRANSFER Registry (15 STEMI hospital networks from 7 European countries)59	2005–2007	≥75 years	382	89.0% vs. 94.4%   P < 0.01	30-day: 11.7% vs. 3.5% P < 0.001
Vital Heart Response (VHR) registry (all hospitals in central and northern Alberta, Canada)60	2006–2011	≥75 years	646	41.2% vs. 45.3%; P = 0.05	In-H: 14.2% vs. 3.8%;   P < 0.001
Bremen Heart Center (Bremen, Germany)61	2006–2014	≥75 years	1248	72.0% vs. 93.8%;   P < 0.001	In-H: 11.8% vs. 4.1%;   P < 0.001
International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC) (41 centres in 12 European countries)62	2010–2015	≥75 years	1315	62.1% vs. 78.9%; P < 0.001	In-H: 19.9% vs. 5.8%; P < 0.001
Oslo University Hospital (Oslo, Norway)63	2005–2011	≥80 years	600	63.5% vs. 73.9%; P < 0.001	In-H: 17.0% vs. 4.0%   P < 0.001
Belgian STEMI registry (72 Belgian hospitals)64	2007–2010	≥80 years	1092	76.9% vs. 85.4%; P < 0.001	In-H: 17.8% vs. 5.5%; P < 0.001
Epworth Hospital (Melbourne, Australia)65	2004–2007	≥85 years	102	8.3% vs. 14.7%; P = 0.025	In-H: 26.6% vs. 3.7%; P = 0.007
Acute Coronary Treatment and Intervention Network Registry-Get With The Guidelines (ACTION-GWTG) database (286 hospitals in North America)66	2007–2008	≥85 years	1845	69.1% vs. 88.0%; P < 0.001	In-H: 19.0% vs. 4.0%; P < 0.001

In-H, in-hospital; pPCI, primary percutaneous coronary intervention.

Evidence in patients with non-ST-elevation-acute coronary syndromes

Evidence of benefit from a routine invasive strategy in older adults with non-ST-elevation (NSTE)-ACS was initially obtained from subgroup analyses of randomized trials in the general NSTE-ACS population, and subsequently from dedicated trials and meta-analyses. In the TACTIS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18) trial,⁷¹ NSTE-ACS patients aged >75 years experienced a relative risk reduction of 56% in death or MI at 6 months in the early invasive arm compared to a conservative strategy, though with higher rates of major bleeding (16.6% vs. 6.5%; P = 0.009) likely because of the routine use of the glycoprotein IIb/IIIa inhibitor tirofiban and the almost universal femoral approach to catheterization. In the subgroup of 839 patients aged ≥75 years included in an individual patient data analysis of the FRISC (Fast Revascularization during Instability in Coronary artery disease) II, Invasive vs. Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of unstable Angina Investigators (RITA)-3 (FIR) trials, the routine invasive strategy was associated with a lower hazard of cumulative adverse events [unadjusted hazard ratio (HR) 0.71, 95% CI 0.55-0.91, P = 0.007] whereas no benefit was observed in patients <65 years (HR 1.11, 95% CI 0.90-1.38, P = 0.33).⁷² In this analysis, the benefit of a routine invasive strategy was observed in men but not in women.

In the Italian Elderly ACS study, 313 patients with NSTE-ACS aged >75 years were randomized upon admission to an early invasive vs. an initially conservative approach and followed up for one year.²⁰ Among patients with elevated troponins, the primary composite endpoint of death, MI, disabling stroke, and repeat hospital stay for CV causes or severe bleeding was significantly reduced with the early invasive approach (HR 0.43, 95% CI 0.23–0.80), whereas no benefit was observed in troponin negative patients. Major bleeding events were rare (<1%). This might be explained by low use of glycoprotein IIb/IIIa antagonists and >70% of trans-radial PCI. In the After Eighty trial, which randomized 557 patients with NSTE-ACS aged ≥80 years to either an invasive or a conservative strategy, the composite one-year endpoint (MI, need for urgent revascularization, stroke, and death) was significantly lower in patients assigned to the invasive group than in the conservative group (HR 0.53, 95% CI 0.41–0.69; P < 0.001).²¹ Radial access was used in 90% of the procedures, with a major bleeding rate of 1.7%. In a meta-analysis of older adults from the TACTIS-TIMI 18,⁷¹ FIR collaboration,⁷² Italian Elderly ACS,²⁰ and After Eighty trials,²¹ patients allocated to the routine invasive strategy experienced a lower risk of death and MI (OR 0.65, 95% CI 0.51–0.83; P < 0.001) at the longest available follow-up (median 36 months) mostly driven by a statistically significant reduction in MI (OR 0.51, 95% CI 0.40–0.66; P < 0.001) and a trend towards a lower death rate, with no heterogeneity among the included studies.⁷³ The incidence of major bleeding was not statistically different between the two strategies. The results of the more recent RINCAL randomized trial, though non-conclusive due to the small size, are in line with these observations.²⁹

Observational data from Italy⁵ and the UK²⁸ confirm that the increased use of invasive treatment among older NSTEMI patients is associated with improved outcome. In particular, the SENIOR-NSTEMI cohort study including data of patients aged >80 years applying a propensity score model showed that at 5 years the adjusted risk of dying was 44% lower with early invasive treatment with the difference emerging from 1 year onwards. Two further RCTs are ongoing in China and the UK on this issue.^{25  ,  30}

Older patients who underwent PCI for ACS were found to experience a greater improvement at 6 months in health-related quality of life than those treated non-invasively.⁷⁴ However, an analysis of patients included in the After Eighty randomized trial, using a similar methodology, failed to show any significant difference at 1 year by comparing an invasive and conservative strategy.⁷⁵

Based upon this evidence, the recently released ESC guidelines on NSTE-ACS recommend for older people to apply the same diagnostic and interventional strategies used for the younger ones (level of evidence IB), considering on an individual case basis ‘ischaemic and bleeding risks, estimated life expectancy, comorbidities, the need for non-cardiac surgery, quality of life, frailty, cognitive and functional impairment, patient values and preferences’.⁷⁶

Treatment of Acute MI-related cardiogenic shock

Cardiogenic shock complicates about 10% of STEMI and 5% of NSTEMI cases among older adults admitted to ICCU, about twice the rate observed in younger patients.⁷⁷ Prompt myocardial revascularization is the only strategy that has been shown to reduce mortality in acute MI-related cardiogenic shock (AMICS)⁷⁸ but in the SHOCK trial seemed to provide no benefit in older adults.⁷⁹ However, as shown by international registries over the last 15 years,^{77  ,  80–82} with the recent increase in early revascularization, AMICS mortality was reduced from 70% to the present 40–50% with the benefit extending across age groups. As shown in Figure 2, the reduction in mortality in older adult AMICS patients observed in the Italian ICCU registries was even larger than that observed in younger patients.⁷⁷ A higher disease burden and multimorbidity in patients treated with a conservative approach have introduced a selection bias which precludes a non-randomized assessment of the benefit of invasive treatment in older adults.⁸³ Among the patients with multivessel coronary disease enrolled in the CULPRIT-SHOCK trial (median age 70 years [interquartile range 60–78], with 214 patients aged ≥75 years), no age per treatment effect interaction was found in the benefit shown by culprit lesion only revascularization in terms or mortality or need for renal replacement therapy.⁸⁴ Therefore, culprit lesion only revascularization can be recommended in older adults with AMICS also considering frailty and comorbidities, particularly pre-existing kidney dysfunction.

Figure 2

Temporal trends in revascularization (upper panel) and in-hospital mortality (lower panel) in older patients with AMI complicated by CS. observed in the Italian intensive coronary care unit registries. AMI, acute myocardial infarction; CS, cardiogenic shock.

The gender issue at old age

The relative proportion of women in the ACS population increases with age but does not equalize with men before the ninth decade. In a recent analysis of ACS admission in Alberta, Canada, women represented 34.3% of the NSTEMI population and 26.5% of the STEMI population, and the mean age was 72 [interquartile range 59–82] years for women, as compared to 61 [53–72] years for men.⁸⁵ This gap may be explained by later development of atherosclerosis among women. In the prospective Ladies ACS study, 645 postmenopausal women and age-matched men with ACS, subdivided in a 2:1 ratio according to four decades of age from 55 to ≥85 years, underwent coronary angiography with core lab angiographic assessment: compared to men, women had about 10 years of delay in coronary atherosclerosis, a gap continuing for decades after menopause.²³ Several reports have examined age-stratified sex disparities in care and outcomes in patients with ACS, showing that sex-based differences in outcome may differ according to age.^{70  ,  86–91}

At younger age, women have lower ACS incidence, but higher mortality as compared to men, for reasons that remain largely unknown.⁹² Both in-hospital and long-term mortality remain higher among women with STEMI, as compared to men, even after adjustment for confounders, whereas outcomes after NSTEMI show less difference.⁹³ These variations in outcome have been attributed to older age and greater burden of comorbidities in women, but also to lower revascularization rates.^{85  ,  94} In an attempt to neutralize these two gaps, an analysis of the Italian Elderly ACS Collaboration on 2035 patients (mean age: 81 ± 4.6 years, 44.4% women) all treated by PCI during index admission still found significantly higher mortality among women with STEMI and among those at first MI, as compared to men, after adjustment for confounders persisting in this age class.⁹⁴

Management of clinical complexity and comorbidities

During the ageing process, individuals become more susceptible to stressors. When stressors overwhelm the homeostatic reserve capacity, geriatric syndromes may develop, consisting in impairments in multiple systems that compromise their compensatory ability. They include several conditions (frailty, multimorbidity, disability, cognitive impairment) which interfere with personal daily life (see Table 3 for specific definitions).^{95  ,  96}

Table 3

Definition of geriatric syndromes

Frailty: Condition associated with increased vulnerability to stressors overwhelming the individual’s reserve capacity, and poor clinical outcomes, including recurrent falls and injuries, hospitalization, and progressive disability.95   Multimorbidity: The concurrent presence of two or more medically diagnosed diseases in the same individual, with the diagnosis of each contributing disease based on established, widely recognized criteria.95   Polypharmacy: Use of five or more medications daily, increasing the chances of adverse drug events and likelihood of harm.96   Disability: Difficulty or dependency in carrying out activities essential to independent living, including tasks needed for self-care and living in a home, and desired activities important to one’s quality of life.95   Cognitive impairment: Condition occurring when a person has trouble remembering, learning new things, concentrating, or making decisions that affect their everyday life.95   Dementia: Severe deterioration of cognitive function characterized by loss of memory, judgement, language, problem-solving and other thinking abilities that are advanced enough to interfere with daily life.95

Chronic kidney dysfunction is one of the most common and strongest independent predictors of mortality in all CV diseases.^{97  ,  98} Among 1904 patients undergoing PCI in the Italian Elderly ACS Collaboration studies, 57% had chronic kidney dysfunction with moderate and 11% with severe renal dysfunction.⁹⁷ After adjustment for the worse baseline variables, moderate dysfunction (HR 1.65, 95% CI 1.01–2.70) and severe dysfunction (HR 2.86, 95% CI 1.52–5.37) were associated with higher one-year mortality.⁹⁷

Increased myocardial fibrosis and cardiac hypertrophy leading to left ventricular dilatation and systolic dysfunction, associated peripheral vascular disease with accelerated vessel calcification may contribute to the higher mortality rate.⁹⁸ Specific evidence-based treatment indications are missing, as chronic kidney dysfunction patients are even less represented than the general elderly population in most clinical trials. Therefore, due to the risk of contrast-induced kidney injury, the rates of coronary angiography and subsequent revascularization are low, particularly in NSTEMI, despite observational data suggesting mortality benefit.⁹⁸

An important, but often overlooked comorbidity, is the presence of valvular heart disease that can be found even in advanced forms in totally asymptomatic patients admitted for ACS. In a post  hoc analysis of the Elderly-ACS 2 trial, moderate-to-severe aortic stenosis or mitral regurgitation was found in 15.9% of the overall study population and significantly impacted on 1-year outcome.⁹⁹

Distinct but often overlapping with comorbidity, frailty may contribute to the development and progression of chronic diseases.^{95  ,  100} Frailty can be assessed using various scales, though an objective assessment may be difficult upon admission for an ACS because most reported measures require patient cooperation.¹⁰¹ Nevertheless. some scales have been used also in large series of older adults with ACS providing useful clinical and prognostic information (Table 4).^101–106 Cognitive impairment is frequently found in frail older patients with MI,^{106  ,  107} a not unexpected finding since many of the established risk factors for coronary artery disease, including diabetes mellitus, smoking, and the metabolic syndrome, as well as atrial fibrillation (AF), have also been identified as potentially modifiable risk factors for development of cognitive decline.^{108  ,  109} In older patients undergoing invasive management for NSTE-ACS, a high prevalence of undiagnosed cognitive impairment (48%) was found at baseline, while 35% of patients experienced cognitive decline during follow-up. Moreover, patients with cognitive impairment were more likely to have major CV events at follow-up with recurrent MI independently associated with further cognitive decline.¹⁰⁸ In these patients, besides guideline-directed management of the acute event, treatment of modifiable risk factors is of utmost importance to prevent recurrences.¹⁰⁹ Patients with frailty and/or cognitive impairment are infrequently enrolled in randomized CV clinical trials, and therefore the evidence of potential benefit of procedural interventions is much weaker than in younger patients.¹⁰⁹ Although frailty does confer a higher bleeding and mortality risk, PCI may provide survival benefit;^110–112 yet any decision about an interventional treatment should be carefully evaluated on an individual basis. More data are needed in this setting before definite conclusions are reached.

Table 4

Frailty scores

Score	Measures	Presence of frailty
Fried score101	Shrinking (unintentional weight loss > 10 lbs in prior year)   Weakness (Grip strength: lowest 20% by gender, body mass index)   Exhaustion (Walking time: slowest 20% by gender height)   Slowness (kcal/week: slowest 20% by gender)	At least 3 criteria
Essential Frailty   Toolset102	Chair rises (0–2 points according to needed time) Cognitive impairment (Minimal Mental Test) (0–1 points)   Hemoglobin levels (0–1 point)   Serum albumin levels (0–1 point)	Most frail: 5 points
Canadian Study of Health and Aging Clinical Frailty Scale103  ,  104	0–7-point scale combining comorbidity, disability, cognitive impairment (clinical judgement)	Most frail: 6–7 points
Frailty score ACTION Registry105	0–6-point scale based on walking, cognition activity of daily living	Moderate to severe frailty: 3–6 points
Columbia score106	0–12 point scale based on serum albumin, handgrip strength, gait speed, Katz activity of daily living	Frailty ≥6 points

Strategies of antithrombotic therapy for secondary prevention

Dual antiplatelet therapy

Optimal P2Y₁₂ receptor inhibition in association with aspirin as dual antiplatelet therapy (DAPT) in older adults with ACS is still controversial, and the registration trials for these drugs included only a minority of older patients. Clopidogrel, though widely prescribed, has a large response variability, resulting in a not negligible proportion of patients with high on-treatment platelet reactivity.¹¹³ The more recent agents prasugrel and ticagrelor have more predictable, and more powerful, ADP-receptor blocking effect. As a consequence, both drugs reduced thrombotic events as compared with clopidogrel, though at higher risk of bleeding, in the respective pivotal studies.^{33  ,  34} Among the older adults enrolled in these trials, prasugrel at 10 mg daily dose significantly increased major bleeding³³ so that the Food and Drug Administration did not recommend its general use in older patients whereas the European Medicines Agency recommended to use a 5 mg/day maintenance dose. On the other hand, the benefit provided by ticagrelor over clopidogrel (including a reduction in CV mortality) was consistent in older adults,¹¹⁴ though with a significant increase in intracranial haemorrhage.³⁴

Specific trials conducted in older ACS patients comparing different P2Y₁₂ inhibitors in association with aspirin have recently been published. The Elderly ACS 2 trial randomized 1443 ACS patients aged ≥75 years who underwent PCI, showing similar rates of major adverse CV events and bleeding complications in patients assigned to prasugrel 5 mg maintenance dose and in those assigned to clopidogrel 75 mg.²⁴ Interestingly, in a post  hoc analysis, prasugrel 5 mg was significantly superior to clopidogrel in reducing thrombotic events in the first month after ACS, whereas clopidogrel was superior to prasugrel 5 mg in reducing late bleedings (31–365 days).¹¹⁵

No benefit was found in the ANTARCTIC (Assessment of a Normal vs. Tailored Dose of Prasugrel After Stenting in Patients Aged >75 Years to Reduce the Composite of Bleeding, Stent Thrombosis and Ischaemic Complications) trial by adjusting the dose of prasugrel after 2–4 weeks based on the results of platelet function testing.²²

A recent network meta-analysis of RCTs that reported separately the results of adults older >70 years showed that prasugrel 5 mg was most likely the best treatment to avoid ischaemic events, whereas clopidogrel showed the highest likelihood of bleeding reduction.¹¹⁶

Among medically managed ACS patients, prasugrel 5 mg showed similar efficacy and safety as clopidogrel 75 mg in the subgroup of older patients of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) study.¹¹⁷

In the POPular AGE trial, clopidogrel significantly reduced bleeding rate (including fatal bleeding) compared with ticagrelor, without any increase in ischaemic events.²⁷ In that trial, ticagrelor was prematurely discontinued in about half of the patients, a finding that could have decreased its potentially beneficial effects, but that also highlights the relevancy of side effects induced by that drug in older adults. In both the Elderly-ACS 2 and POPular AGE trials, ischaemic and bleeding event rates at 1 year observed in the clopidogrel-randomized patients were far lower than those found in the clopidogrel-randomized older patients included in the TRITON-TIMI 38 and PLATO trials.¹¹⁸ In a recent analysis of the SWEDEHEART registry on 14 005 patients aged ≥80 years who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after MI, ticagrelor use was associated with a significantly higher risk of death (HR 1.17, 95% CI 1.03–1.32) and bleeding (HR 1.48, 95% CI 1.25–1.76) compared with clopidogrel after Cox regression adjustment.¹¹⁹

The recently released ESC guidelines on NSTE-ACS recommend 12-month DAPT with the use of a potent P2Y₁₂ receptor inhibitor (prasugrel/ticagrelor) unless a high bleeding risk (HBR) is present.⁷⁷ In HBR patients, clopidogrel should be added to aspirin for 3 months (or just for one month if bleeding risk is very high) and then a single agent should be prescribed.⁷⁷ HBR can be assessed using either the ARC criteria or the PRECISE-DAPT score (with a value ≥25 indicating HBR). Most older patients fulfill the criteria for HBR using both ARC criteria and the PRECISE-DAPT score:¹²⁰ in the Elderly-ACS 2 trial, two thirds of patients met the ARC-HBR criteria and 77% had a PRECISE-DAPT score >25.¹²¹

Therefore, following guidelines, the great majority of ACS patients with advanced age should be treated with short-term DAPT (3–6 months), preferably using clopidogrel combined with low-dose aspirin. According to the results of the SENIOR trial, this approach should be preferred even in patients receiving a drug-eluting stent.²⁶ A case-by-case decision based not only on the assessment of the bleeding risk but also of the ischaemic risk seems the most reasonable option for the clinician to choose the composition and the duration of DAPT.

Combined antiplatelet and anticoagulant treatment

Properly balancing the efficacy-to-safety ratio of antithrombotic therapies in older adults is challenging especially when combined antiplatelet and oral anticoagulant (OAC) therapy is needed, as is the case of concomitant AF and ACS, a condition occurring in approximately 10% of STEMI patients and 13% of NSTE-ACS patients aged ≥75 years.¹²² In this setting, dual antithrombotic therapy (DAT) with OAC, either vitamin K antagonist or direct OAC (DOAC), and single antiplatelet therapy (SAPT), essentially clopidogrel, is significantly safer than triple antithrombotic therapy (TAT) with vitamin K antagonist, aspirin and clopidogrel, without significant excess in ischaemic cardiac and/or cerebrovascular adverse events,^123–127 irrespective of whether the clinical presentation is ACS or stable coronary artery disease.¹²⁸ The safety benefit of contemporary DAT vs. TAT is attributable to both the lower number of antithrombotic drugs and the use of a DOAC, which should always be regarded as the preferred OAC.¹²⁹ Since a trend towards an (early) increase in stent thrombosis and MI is apparent with DAT,¹³⁰ an initial, short (few days to few weeks) course of TAT following PCI is now routinely recommended.¹³¹ Longer durations, up to 6 months, of TAT may be carefully considered when there are no additional major ARC-HBR criteria, and the risk of ischaemic complications is predominant and life-threatening as in unintended suboptimal PCI result (e.g. stent under-expansion and/or two-stent PCI of left main bifurcation especially if no final kissing balloon could be performed).^{132  ,  133}

Duration of subsequent DAT should be individualized based on the balance between ischaemic and bleeding risk, and generally comprised between 6 and 12 months.¹³⁴

In the four pivotal RCTs comparing DAT (with DOAC) and TAT, older patients were under-represented, being about one third in PIONEER AF-PCI¹²⁴ and in RE-DUAL PCI,¹²⁵ and not reported in AUGUSTUS¹²⁶ and ENTRUST AF-PCI.¹²⁷ In a dedicated sub-analysis of the RE-DUAL PCI trial¹³⁵ where patients were age stratified at 75 years, the safety benefit of DAT with dabigatran 110 mg compared to TAT was preserved in older patients, whereas the risk of thromboembolic events tended to be higher. No clear safety benefit was observed for DAT with dabigatran 150 mg compared to TAT in older patients, in whom also the effect on thromboembolic events was similar.

Up to one-third of patients with ACS do not undergo PCI,³¹ and more than half of these are older than 75 years: in a sub-analysis of the AUGUSTUS trial, where 39% of AF patients presenting with ACS were treated medically, DAT appeared the preferred antithrombotic therapy also in this context.¹³⁶

Upon completion of the DAT course, lifelong (D)OAC monotherapy is recommended, unless clinical and/or procedural features of increased ischaemic risk are present.¹³⁴ The results of the randomized AFIRE trial¹³⁷ (carried out in Japan where the approved doses are 15 or 10 mg according to creatinine clearance) support the use of rivaroxaban monotherapy over the combination of rivaroxaban and SAPT (aspirin in 70% of cases), owing to the superior safety and non-inferior efficacy. Although the mean age of patients enrolled in the AFIRE trial was 74 years, no significant interaction of age, above vs. below 75 years, was observed regarding both efficacy and safety.

Other secondary prevention measures

Atherosclerotic risk factors are highly prevalent among older men and women with ACS, frequently occurring in clusters and in association with a substantial comorbidity burden. Lifestyle modifications are important to improve blood pressure control and achieve glycaemic and cholesterol targets.¹³⁸ The clinical benefits from medical secondary preventive therapies in older patients are still a matter of debate. In general, drug prescription follows the recommendations of guidelines for younger patients, however with observed fewer prescriptions in patients with comorbidities, frailty and cognitive deterioration treated conservatively.¹³

As for younger patients, beta-blockers should be considered in case of large anterior MI, left ventricular systolic dysfunction, clinical or instrumental evidence of tachyarrhythmias, with great caution due to the higher risk of bradyarrhythmia. Moreover, in the management of hypertension, beta-blockers have been shown to be less effective as compared to other classes of anti-hypertensive drugs.¹³⁹

Use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers is associated with mortality benefit in older patients with large MI and left ventricular dysfunction.^140–143 When possible, older adults should be titrated to the higher doses of ACE inhibitor¹⁴³ with regular monitoring of serum potassium levels and kidney function, discontinuing treatment only if creatinine increases by >30% from baseline during the first 2 months of therapy.¹⁴⁴

Recent data confirm the efficacy and safety of lowering LDL cholesterol in older patients: a large meta-analysis showed a significant reduction in major vascular events, including CV death, myocardial infarction, stroke, and coronary revascularization.¹⁴⁵ Therefore, advanced age, despite the shorter life expectancy as compared to younger patients, should not be considered a criterion for less aggressive cholesterol lowering treatment, as largely recommended by recent guidelines.

Exercise for increasing physical activity is an important component of secondary prevention. Older adults are generally under-represented in secondary prevention exercise programs due to low physicians referral because of low functional capacities, multiple comorbidities and reluctancy to enter a structured exercise program.¹⁴⁶ However, when activities are individually tailored, also frail patients may have physical, cognitive, and psychological benefit, enhancing self-esteem and functional independence.¹⁴⁷ In a randomized trial, a regular exercise intervention programme as compared with a control group improved quality of life with a reduced perception of anxiety or depression.¹⁴⁷

In conclusion, older adults are a special high-risk population with its own peculiarities in terms of biological vulnerability, risk stratification assessment and management approaches. Solid evidence has been obtained over the last decade about the positive effect of an early invasive approach across the ACS spectrum, with a clear reduction in mortality. Open issues for investigation remain the strategy, either conservative or invasive, to adopt in patients with advanced degrees of frailty, optimal combination and duration of DAPT and the value of complete vs. culprit only revascularization, particularly in NSTEMI patients.¹⁴⁸ A case-by-case decision supported by a holistic vision should always been considered (Figure 3).

Figure 3

Optimized management in older patients admitted for acute coronary syndrome.

Author’s contribution

(1) Substantial contributions to the conception and design (S.S., S.D.S., N.M.) and interpretation of data drawn from the literature (A.R., G.C., M.V., L.D.L., G.D.L.); (2) drafting the article (N.M., S.D.S., S.S., G.C., A.R., L.D.L., C.M., R.D.R.), revising it critically for important intellectual content (G.D.L., M.V., S.D., S.S.); and (3) final approval of the version to be published (all).

Conflict of interest: N.M. reports lecture fees Pfizer/Bristol-Myers Squibb and grant research from Getinge Global USA, outside of the submitted work. G.C. reports lecture fees and/or consulting for AstraZeneca, Bayer, Boehringer Ingelheim, Philips Healthcare, and Daiichi Sankyo. L.D.L. reports lecture fees and/or consulting for AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, Eli Lilly, Pfizer/Bristol-Myers Squibb, and Sanofi. A.R. reports lecture fees and/or consulting for AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer BMS. M.V. reports personal fees from AstraZeneca, grants and personal fees from Terumo, personal fees from Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Opsens, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel | Dept. Klinische Forschung, Vifor, Bristol-Myers Squib SA, iVascular, Medscape, and Biotronik, outside the submitted work. S.S. reports personal fees from Bayer, Abbott, and AstraZeneca, outside the submitted work. C.M., S.D.S., and R.D.R. have nothing to disclose.