Review Article
Acute Coronary Syndrome Among Older Patients A Review Murugapathy Veerasamy, MBBS, MRCP,*† Richard Edwards, PhD,† Gary Ford, FRCP,* Tom Kirkwood, PhD,‡ Julia Newton, PhD, FRCP,*‡ Dave Jones, MD, FRCP,* and Vijay Kunadian, MBBS, MD, FRCP*†
Abstract: Ischemic heart disease is the leading cause of mortality worldwide. Due to advances in medicine in the past few decades, life expectancy has increased resulting in an aging population in developed and developing countries. Acute coronary syndrome causes greater morbidity and mortality in this group of older patients, which appears to be due to age-related comorbidities. This review examines the incidence and prevalence of acute coronary syndrome among older patients, examines current treatment strategies, and evaluates the predictors of adverse outcomes. In particular, the impact of frailty on outcomes and the need for frailty assessment in developing future research and management strategies among older patients are discussed.
and retrospective studies were included. Cross-references from the citation lists were examined and included for relevant material.
PREVALENCE OF ACS AMONG OLDER PATIENTS
schemic heart disease (IHD) is the leading cause of death worldwide.1 There is a steep increase in mortality due to IHD among those >70 years of age.2 There has been rapid progress in the management of acute coronary syndrome (ACS) over the past decade with the use of adjunctive pharmacotherapy, specifically novel antiplatelets and anticoagulants, and advanced percutaneous coronary intervention (PCI) procedures with drug-eluting stents becoming common place.3–6 These medical and technical advancements have led to improved survival and gains in life expectancy, especially in younger persons (75 years of age (n = 55,028) died from IHD compared to younger individuals 70 years represented 49% of patients with an MI in the MINAP data. The average age for a first STEMI was 65 years, while that of non-STEMI (NSTEMI) was 70 years (21% of STEMI patients and 26% of NSTEMI patients were between 70 and 79 years of age, in comparison to 15% of patients with STEMI and 27% of patients with NSTEMI who were 80–89 years of age). Although cases of STEMI appear to be equally distributed around the age-range 60–69 years, for NSTEMI the majority present older than this age.8 In the Global Registry of Acute Coronary Events (GRACE),9 increasing age was associated with increased incidence of NSTEMI. NSTEMI was diagnosed in >30% of patients aged 75 years). All in-hospital events after ACS were more frequent among elderly patients. Cardiogenic shock was nearly 6 times more common in the oldest compared with the youngest group (9.8% vs 1.6%, respectively). Rates of major bleeding were twice more in patients aged ≥85 years compared to 75 years were excluded from many trials that compared fibrinolysis against primary PCI on the basis of age.12 There is no clear consensus on the optimal reperfusion strategy to use in the elderly due to lack of clinical trial data and details of comorbidities.13 From subgroup analysis, primary PCI has better outcomes compared to fibrinolysis in older patients as seen in the Global Utilization of Streptokinase and Tissue Plasminogen Activator (TPA) for Occluded Coronary Arteries (GUSTO) IIb trial in which approximately 15% were >75 years.14
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Coronary Disease in Older Patients
TABLE 1. Reperfusion Strategy in Older Patients With STEMI Study De Boer et al15 PPCI versus Thrombolysis Goldenberg et al16 PPCI versus Thrombolysis
Age Group
Number of Patients
>75 years
87
≥70 years
130
Bueno et al17 TRIANA trial PPCI versus thrombolysis
≥75 years
266
GRACE Registry subgroup18 PPCI versus Thrombolysis
≥70 years
1134
70–80 years and >80 years
6763
De Boer et al19 Meta-analysis PPCI versus Thrombolysis
Outcomes Composite of death, MI and stroke at 30 days: 9% vs 29% P = 0.01; at 1 year: 13% vs 44% P = 0.001 Combined end point of death, reinfarction, or revascularization for recurrent ischemia 29% vs 93%, P < 0.01 Significant reduction in the rates of the composite end points of death, reinfarction, or disabling stroke with PPCI, OR 0.64, 95% CI 0.45–0.91, P = 0.013 In-hospital complications: mortality 13.5% vs 14.8%, reinfarction 1.1% vs 5.7%, cardiogenic shock 11.3% vs 11.6%, major bleeding 8.6% vs 5.9%, and stroke 1.1% vs 2.8% 30-day mortality, MI, or stroke; 70–80 years: 12.5% vs 24.2, OR 0.45, 95% CI: 0.34–0.59; >80 years: 23.3 vs 35.1, OR 0.56, 95% CI: 0.36–0.86
CI indicates confidence interval; GRACE, Global Registry of Acute Coronary Events; MI, myocardial infarction; OR, odds ratio; PPCI, primary percutaneous coronary intervention.
Few studies have been conducted specifically for elderly patients with STEMI. In a study by de Boer et al,15 87 patients >75 years old with acute MI were assigned to PCI or thrombolysis with intravenous streptokinase. There was a significant increase in the incidence of death, reinfarction, and stroke at 30 days [29% vs 9%, relative risk (RR): 4.3, 95% confidence interval (CI) 1.2–20.0, P = 0.01) and 1 year (44% vs 13%, RR: 5.2; 95% CI 1.7–18.1, P = 0.001) in the thrombolysis group compared with the PCI group. Goldenberg et al16 compared 130 consecutive ≥70 years old patients with STEMI after assigning them to receive either primary PCI or thrombolysis with TPA. At 6 months, patients treated with primary PCI, compared with those treated with thrombolytic therapy, had a trend toward lower incidence of reinfarction (2% vs 14%, P = 0.053), and significant reductions in the rates of revascularization for recurrent ischemia (9% vs 61%, P < 0.001) and in the combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < 0.01). Rates of major bleeding were also significantly reduced in the group receiving primary PCI (0% vs 17%, P = 0.03). In the TRatamiento del Infarto Agundo de miocardion eN Ancianos (TRIANA) study,17 a randomized, controlled trial involving 266 patients >75 years of age (mean age 81), patients received either primary PCI (n = 134) or fibrinolysis (n = 132). In this trial, which was ceased prematurely due to difficulties in recruitment, the rates of the composite trial end point of all-cause mortality, reinfarction, or stroke were lower in the group receiving primary PCI compared to those receiving fibrinolysis, but statistical significance was not reached (OR 0.69, 95% CI 0.38–1.23, P = 0.21). In a pooled analysis, primary PCI compared with thrombolysis demonstrated no overall mortality reduction among patients receiving primary PCI compared to those receiving fibrinolysis (OR 0.74, 95% CI 0.49–1.13, P = 0.16). However, there was a significant reduction in the rates of the composite end points of death, reinfarction, or disabling stroke with primary PCI (OR 0.64, 95% CI 0.45–0.91, P = 0.013). The GRACE registry demonstrated lower adjusted in-hospital mortality (OR 0.62; 95% CI 0.39–0.96) for primary PCI compared with fibrinolysis among 2975 patients with STEMI who were aged ≥70 years.18 In a meta-analysis of 22 randomized, controlled trials (n = 6763), 30-day mortality increased with increasing age and ranged from 1.1% in the fibrinolysis group and 1.8% in the primary PCI group in patients ≤50 years, to 26.4% and 18.3% in patients >80 years of age. In this analysis of randomized trials,19 the reduction in clinical end points of death, MI, and stroke by primary PCI was not influenced by age. In octogenarians who comprised 6% of the patients in © 2014 Lippincott Williams & Wilkins
the meta-analysis, those who were randomized to primary PCI had a lower incidence of mortality (18.3% vs 26.4% events; P = 0.049) than their counterparts who were randomized to fibrinolysis. However, there was no difference in the occurrence of repeat MI (3.9% vs 7.0%; P = 0.18) and stroke (5.8% vs 7.9%; P = 0.45).19 These studies suggest that among older patients presenting with STEMI, primary PCI is the optimal revascularization strategy.
Revascularization Strategy in NSTEMI In the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) study,20 patients aged >65 years who were treated with an early invasive approach of catheterization within 4–48 hours and revascularization if appropriate had a lower risk of death, subsequent MI, or rehospitalization for ACS at 6 months than patients who underwent a conservative strategy of revascularization only with objective evidence of ischemia (14.9% vs 17.8%, respectively). However, this was not statistically significant.20 From the CRUSADE Quality Improvement Initiative,21 the unadjusted incidence of in-hospital mortality for all patients (n = 17926) was 2.0% for patients who underwent early invasive management within 48 hours compared with 6.2% for patients who did not undergo early invasive management [adjusted hazard ratio (HR): 0.63, 95% CI 0.52–0.77]. In this study, younger and healthier patients generally received the benefit of early invasive management, whereas older patients with more comorbidities and a greater likelihood to benefit from invasive treatment for NSTEMI were more likely to be managed conservatively.21 In the Acute Coronary Syndromes Registry study,22 1936 patients ≥75 years with NSTEMI were included and analyzed by 2 groups. One thousand five patients underwent coronary angiography and revascularization if indicated, and 931 patients received conservative treatment. The mean age was 78.7 years versus 82.2 years (P < 0.0001) and women comprised 48.3% versus 58.6% (P < 0.0001) of each group, respectively. In-hospital mortality and the combined end point of death or non-fatal reinfarction were lower in the patients undergoing invasive management compared with the group managed by conservative strategy (6.0% vs 12.5%, P < 0.0001 and 9.6% vs 17.3%, P < 0.0001, respectively). There was a significant reduction in 1-year mortality in the invasive treatment group compared to the conservative treatment group (OR 0.56, 95% CI 0.38–0.81).22 In a recent study comparing the different management strategies used among patients >75 years of age between 2 different www.cardiologyinreview.com | 27
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cities (Goteborg [Sweden] and Minneapolis St Paul [USA]), it was observed that in Goteborg a smaller proportion of patients received PCI (7.3% vs 32.8%; P < 0.0001 among men, 6.6% vs 29.4%; P < 0.0001 among women).23 Subsequently, survival after 7.5 years follow-up was observed to be lower in Goteborg (17.5% vs 26.6%, [OR for survival at follow-up: 0.66, 95% CI: 0.50–0.88] among men and 17.0% vs 28.8% [OR 0.49, 95% CI 0.36–0.67] among women). While the increased survival rate was thought to be attributable, at least in part, to the increased utilization of PCI in the Minneapolis cohort, it should be noted that several other factors could have contributed, such as differences in medical management and other geographical variables.23 In the Italian Elderly ACS study, 313 non-ST elevation ACS patients ≥75 years old were randomized to an early aggressive approach or initial conservative approach.24 In the early aggressive treatment group, 88% of patients underwent coronary angiography and 55% had PCI, and in the initial conservative group it was 29% and 23%, respectively. There was a significant reduction in the primary end point (death, MI, stroke, and rehospitalization for cardiovascular causes) in the early aggressive treatment group with raised troponin on admission compared to conservative approach at 1 year (HR 0.43; 95% CI 0.23–0.80, log rank P < 0.05), while there was no difference noted between the 2 groups with normal troponin on admission. Overall, these studies suggest that there may be better outcomes with an early invasive management strategy in the elderly population in carefully selected patients presenting with NSTEMI compared with conservative medical therapy.
PCI Versus Coronary Artery Bypass Grafting Older patients are more likely than younger patients to have 3-vessel disease.25 In a retrospective study of 10,141 ACS patients with multivessel disease who were ≥85 years (mean age 87.2 years), patients were followed up for 3 years after either coronary artery bypass grafting (CABG) or multivessel PCI. Although lower survival was noted in the early months after CABG compared to PCI (OR 1.48, 95% CI 1.34–1.64, P < 0.01), CABG provided significantly better survival (OR 0.60, 95% CI 0.53–0.69, P < 0.05) and freedom from the composite outcome of death, repeat revascularization, stroke, and acute MI at 36 months (OR 0.83, 95% CI 0.76–0.91, P < 0.01).26 Long-term outcomes were poor in patients with heart failure, lung disease, and peripheral vascular disease in the CABG group. In a meta-analysis of 10 randomized, controlled trials by Flather et al,25 over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age. CABG led to an increased risk of mortality among patients in the lowest tertile for age (n = 2602, mean age 49.8), with adjusted CABG to PCI HR of 1.23 (95% CI 0.95–1.59). However, in the middle tertile (n = 2602, mean age 61.0), the HR was 0.89 (95% CI 0.73–1.10), favoring CABG. In the oldest tertile (n = 2602, mean age 70.5), the HR decreases further to 0.79 (95% CI 0.67–0.94). It was observed that above 59 years of age, the HR fell to 75 years of age is lacking.
DOES THE POPULATION STUDIED REFLECT THE POPULATION TREATED? Evidence from clinical trials to inform the management of ACS in older patients is limited. More than half of all trials for coronary disease in the past decade failed to enroll patients >75 years of age, with this subgroup accounting for just 9% of all patients enrolled in trials.30 Analysis from the CRUSADE Quality Improvement Initiative demonstrated that among a community population with non-ST-elevation ACS, patients who were enrolled in a clinical trial (2.5% of the overall CRUSADE population) were younger (median 65 vs 68 years), more often male (67.9% vs 59.3%), had less renal insufficiency (8.5% vs 13.5%), and had less heart failure (13.2% vs 19.0%) than those not enrolled in trials.31 Evidence-based recommendations from trials do not account for the age-related differences in physiology and disease that may alter these relationships. The age gap between trials and community populations begins at age 75 years and widens with age.32 Even the older patients included in trials are different from the older patients in the community. Trial populations have lower rates of traditional cardiovascular risk factors, less comorbidity, and better renal function in each age subgroup than do community populations.31 As older patients are at increased risk from cardiac events, the absolute benefit of treatment should increase if treatment risks can be balanced against benefits.33 Risks and benefits derived from trials cannot always be extrapolated to older patients in daily clinical practice due to the differences between the patient groups.34 The current evidence in the management of older ACS patients is limited due to the less number of older patients in the randomized trials.
PREDICTORS OF POOR OUTCOMES IN OLDER ACS PATIENTS Age Adverse events following ACS increase with age.11,19,35–37 RR of in-hospital death among ACS patients increased by 70% on average for each 10-year increase in age (OR 1.70, 95% CI, 1.52–1.82).37 This association remains even after accounting for confounding factors, such as heart rate, systolic blood pressure, serum creatinine, electrocardiographic changes, cardiac arrest, and history of diabetes or hypertension.
Comorbidities The decision to intervene in older ACS patients need to be balanced against the general health and comorbidities of these patients.34 Old age is not an isolated risk factor especially when age-associated conditions, such as anemia, kidney disease, frailty, disability, and cognitive dysfunction, have an impact on the outcomes of ACS management. In addition, diminished organ reserves and abnormal functional and cognitive status influence the nature of disease presentation, response to treatment, and recovery.32 Renal dysfunction is © 2014 Lippincott Williams & Wilkins
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associated with an increased risk of bleeding in older populations.38 Old age-related functional and cognitive changes have an impact on disease-related risks, which needs to be assessed in the management of older ACS patients.
Frailty Declining physiological reserve and resulting impaired resistance to stressors lead to frailty syndrome.39 Twenty-five to 50% of patients with cardiovascular disease can be identified as frail, depending on the frailty scale used and the population group studied.40 The cause for decline in physiological reserve is multifactorial and involves multiple organ systems. Frailty has become increasingly relevant in the field of cardiovascular medicine as the patient population is aging, and also there is increasing evidence of the association between cardiovascular disease and frailty, both at the mechanistic level and the epidemiologic level.41 Activities of daily living (ADL), physiological reserves, nutritional status (albumin, weight loss), and functional status are all important markers of older patients at increased risk of morbidity and mortality.42 Altered cognition, hearing, and vision may delay presentation and result in increased risks due to delays in commencing interventional treatment. Impaired communication affects decision making, and these patients would find it difficult to adhere to a treatment plan and consent for invasive procedures. As frailty includes a number of components, a better understanding of age-related health issues separate from diseaserelated risk is needed.43 Frailty is not reflected by disabilities in ADL (eg, getting dressed unassisted) or instrumental ADL (such as going shopping unassisted) alone. Frailty occurs earlier than disability and can be elicited in a large number of well-functioning older adults. Disability can be viewed as the end-result of long-standing frailty and comorbidity burden.40 Although there is a overlap between frailty, disability, and comorbid conditions, these represent distinct domains.43 Frailty can be assessed by a number of clinical instruments and scores.44,45 The variables measured include physical inactivity, strength, exhaustion, comorbid conditions, and cognitive impairment as main components. A task force on frailty assessment in older people suggested that gait speed could represent the most suitable instrument to be implemented in both research and clinical evaluation of older people to assess frailty.44 The 5-minute gait speed test is a simple and effective way of objectively measuring frailty in patients with cardiovascular disease and should be incorporated in risk assessment. Fried et al46 used data from the Cardiovascular Health Study to develop a tool for the assessment of frailty among adults aged ≥65 years. Participants (n = 5317) ≥65 years were assessed annually. Examinations and surveillance were conducted assessing the presence of incident disease, hospitalization, falls, disability, and mortality. Frailty was defined as “a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 pounds in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity.” According to the above criteria, 6.9% of the study population were frail. The prevalence increased with increasing age and was greater in women than in men. Over a 3-year period, frailty was independently associated with increased falling incidents, worsening mobility, disability in ADL, hospitalization, and mortality. The presence of 1 or 2 of the Fried frailty criteria indicating intermediate frail status showed an intermediate risk of these outcomes and an elevated risk of becoming frail over a period of 3 to 4 years. Rockwood et al47 developed the 7-point Clinical Frailty Scale (category 1: very fit—robust, active, energetic, well motivated, and fit; these people commonly exercise regularly and are in the most fit group for their age to category 7: severely frail—completely © 2014 Lippincott Williams & Wilkins
Coronary Disease in Older Patients
dependent on others for their ADL, or terminally ill) and used it to measure frailty in 2305 elderly patients participating in the Canadian Study of Health and Aging. After adjustment for age, sex, and education, each 1-category increment of the clinical frailty scale significantly increased the risks of death (21.2%, 95% CI 12.5–30.6%) and entry into an institution (23.9%, 95% CI 8.8–41.2%) within 6 years.
Markers Associated With Frailty Chronic low-grade inflammation plays a common role in pathways leading to cardiovascular disease and frailty. Circulating inflammatory markers such as neutrophils, monocytes, high sensitivity C-reactive protein, and interleukin-6 are increased in cardiovascular disease and frailty.48–51 Another common pathway in the development of cardiovascular and frailty is insulin resistance. Independent of its contribution to chronic inflammation, insulin resistance leads to impaired muscle protein breakdown, which in turn leads to reduced availability of amino acids for maintenance and repair functions.52,53
Frailty and Poor Cardiovascular Outcomes Frail patients with cardiovascular disease, especially those undergoing invasive procedures or experiencing coronary artery disease and heart failure, are more likely to experience major cardiovascular events and death compared to their non-frail counterparts.40 Several studies have demonstrated an association between frailty and cardiovascular disease in community-dwelling older adults.54–59 The prevalence of frailty in older patients with cardiovascular disease is displayed in Table 2. Frailty is a powerful predictor of adverse cardiovascular outcomes and hence, frailty measures should be routinely used in cardiovascular risk assessment. This is especially important in the management of ACS.
Frailty in the Setting of NSTEMI In a study of 307 hospitalized NSTEMI patients ≥75 years of age, 149 (48.5%) were considered frail by the 7-point frailty criteria of Rockwood et al.47 A lesser number of frail patients underwent coronary angiography compared to non-frail patients. Frailty was independently associated with the risk of major adverse cardiovascular (death from any cause, myocardial reinfarction, revascularization due to ischemia, hospitalization for any cause, major bleeding, stroke/transient ischemic attack, and need for dialysis) outcomes (OR 2.2; 95% CI 1.3–3.7), in-hospital mortality (OR 4.6; 95% CI 1.3–16.8), and 1-month mortality (OR 4.7; 95% CI, 1.7–13.0). From this study, Ekerstad et al60 concluded that frailty was strongly and independently associated with in-hospital mortality, 1-month mortality, and prolonged hospital care. Similarly, in the 1-year follow-up of this study, there was increased mortality in frail patients compared with non-frail patients (HR 4.3, 95% CI 2.4–7.8).61
Frailty in Patients Undergoing PCI In a prospective cohort study by Singh et al,62 frailty (as defined by the frailty score by Fried et al46) was added to conventional cardiovascular risk factors in the Mayo Clinic Risk Score. Frailty was associated with increased long-term mortality or MI (HR 2.45; 95% CI 1.33–4.53) among patients undergoing PCI. The authors concluded that the addition of frailty, comorbidity, and quality of life significantly improves the prognostic ability of the Mayo Clinic Risk score.62
FUTURE DIRECTIONS Limited clinical randomized controlled trial data to guide acute care in older patients and the uncertainty about risk-benefit assessment with advanced age is likely to explain the underuse of appropriate medications and invasive treatment strategies.30 Older patients who are at high risk of adverse outcomes following ACS are underrepresented in clinical trials, despite the fact that older patients constitute www.cardiologyinreview.com | 29
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TABLE 2. Prevalence of Frailty in Older Patients With CVD Design
Number of Patients
Women’s Health and Aging Studies I and II (WHAS I and II)54 Zutphen Elderly Men’s Study55 French 3 city Study56
Study
Secondary analysis
670
Frailty (Fried), prevalent CVD, 3-year mortality
Key Variables
Community dwellers
Population
OR 2.72 (95% CI 1.72–4.30)
Secondary analysis
450
Community dwellers
OR 4.1 (95% CI 1.8–9.3)
Prospective cohort
3208
Community dwellers
Beaver Dam Eye Study57
Secondary analysis
2962
Cardiovascular Health Study (CHS)58
Secondary analysis
4735
OR 3.00 (95% CI 1.65–5.57) OR 2.67 (95% CI 1.33–5.41) OR 2.79 (95% CI 2.12–3.67)
Purser et al59
Prospective cohort
309
Frailty (Chin), prevalent CVD, 3-year mortality Gait speed, CVD events and mortality Frailty (Klein), prevalent CVD, 10-year mortality Frailty (Fried), prevalent CVD, subclinical CVD, 7-year mortality Frailty (Fried, Rockwood, gait velocity), 6-month mortality
Community dwellers Community dwellers In-patients with severe coronary artery disease
Frailty, CVD, Mortality
OR 4.0 (95% CI 1.1–13.8)
CI indicates confidence interval; CVD, cardiovascular disease; OR, odds ratio.
a significant proportion of the patient population and are more likely to benefit from treatment strategies due to higher risk.32,63 For gains in quality life-years following ACS to continue, survival from acute heart disease will need to also extend to the very older population.64,65 It is important to understand the risks and benefits of treatment in this group to improve outcomes. Frailty assessment might usefully be incorporated into the management of older patients with ACS. Future large-scale randomized studies evaluating novel therapies in addition to contemporary care are required for the aging patients presenting with ACS. A study is currently underway consisting of older patients presenting with ACS and undergoing PCI to evaluate predictors of poor quality of life and adverse outcomes following PCI and to develop an integrated risk score to predict outcomes and inform clinical decision making (UKCRN ID 12742, NCT 01933581).
CONCLUSION Older patients constitute a significant group of ACS patients. With increasing life expectancy and advances in medicine, the proportion of older patients presenting with ACS will increase. The older high-risk patients who are likely to benefit most from current pharmacotherapy and invasive procedures for ACS are managed conservatively due to the difficulty in risk-benefit assessment. This is a result of a lack of clear evidence due to underrepresentation of this older group in clinical trials. It is important to recognize that chronological age does not always reflect biological age. Frailty, functional status, and social aspects are not routinely assessed in older ACS patients. Future trials should enroll a greater proportion of older patients to reflect the real world population needing treatment and assess and report frailty status of trial participants. Standard reporting of age groups across trials and registries is needed to facilitate comparisons and pooling of data. A better understanding and phenotyping of older patients presenting with ACS are required. Prospective trials performed exclusively in the older patients will be of help in assessing the benefits and safety of pharmacotherapy and invasive procedures. ACKNOWLEDGMENT This research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. 30 | www.cardiologyinreview.com
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Effectiveness of primary percutaneous coronary intervention compared with that of thrombolytic therapy in elderly patients with acute myocardial infarction. Am Heart J. 2004;147:253–259. 19. de Boer SP, Westerhout CM, Simes RJ, et al; Primary Coronary Angioplasty Versus Thrombolysis-2 (PCAT-2) Trialists Collaborators Group. Mortality and morbidity reduction by primary percutaneous coronary intervention is independent of the patient’s age. JACC Cardiovasc Interv. 2010;3:324–331. 20. Cannon CP, Weintraub WS, Demopoulos LA, et al; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)–Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/ IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879–1887. 21. Bhatt DL, Roe MT, Peterson ED, et al; CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-STsegment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA. 2004;292:2096–2104. 22. Bauer T, Koeth O, Jünger C, et al; Acute Coronary Syndromes Registry (ACOS) Investigators. Effect of an invasive strategy on in-hospital outcome in elderly patients with non-ST-elevation myocardial infarction. Eur Heart J. 2007;28:2873–2878. 23. Smith LG, Herlitz J, Karlsson T, et al. International comparison of treatment and long-term outcomes for acute myocardial infarction in the elderly: Minneapolis/ St. Paul, MN, USA and Goteborg, Sweden. Eur Heart J. 2013;34:3191–3197. 24. Savonitto S, Cavallini C, Petronio AS, et al; Italian Elderly ACS Trial Investigators. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial. JACC Cardiovasc Interv. 2012;5:906–916. 25. Flather M, Rhee JW, Boothroyd DB, et al. The effect of age on outcomes of coronary artery bypass surgery compared with balloon angioplasty or baremetal stent implantation among patients with multivessel coronary disease. A collaborative analysis of individual patient data from 10 randomized trials. J Am Coll Cardiol. 2012;60:2150–2157. 26. Sheridan BC, Stearns SC, Rossi JS, et al. Three-year outcomes of multivessel revascularization in very elderly acute coronary syndrome patients. Ann Thorac Surg. 2010;89:1889–1894; discussion 1894–1885. 27. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373:1190–1197. 28. Artinian NT, Duggan C, Miller P. Age differences in patient recovery patterns following coronary artery bypass surgery. Am J Crit Care. 1993;2:453–461. 29. Slater JP, Guarino T, Stack J, et al. Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery. Ann Thorac Surg. 2009;87:36–44. 30. Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA. 2001;286:708–713. 31. Kandzari DE, Roe MT, Chen AY, et al. Influence of clinical trial enrollment on the quality of care and outcomes for patients with non-ST-segment elevation acute coronary syndromes. Am Heart J. 2005;149:474–481. 32. Alexander KP, Newby LK, Cannon CP, et al; American Heart Association Council on Clinical Cardiology; Society of Geriatric Cardiology. Acute coronary care in the elderly, part I: Non-ST-segment-elevation acute coronary syndromes: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2549–2569. 33. Alter DA, Manuel DG, Gunraj N, et al. Age, risk-benefit trade-offs, and the projected effects of evidence-based therapies. Am J Med. 2004;116:540–545. 34. Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of disease specific guidelines for patients with multiple conditions. N Engl J Med. 2004;351:2870–2874.
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35. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation. 2000;101:2557–2567. 36. Eagle KA, Lim MJ, Dabbous OH, et al; GRACE Investigators. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291:2727–2733. 37. Granger CB, Goldberg RJ, Dabbous O, et al; Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med. 2003;163:2345–2353. 38. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J. 2003;24:1815–1823. 39. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm–issues and controversies. J Gerontol A Biol Sci Med Sci. 2007;62:731–737. 40. Afilalo J. Frailty in Patients with Cardiovascular Disease: Why, When, and How to Measure. Curr Cardiovasc Risk Rep. 2011;5:467–472. 41. Afilalo J, Karunananthan S, Eisenberg MJ, et al. Role of frailty in patients with cardiovascular disease. Am J Cardiol. 2009;103:1616–1621. 42. Ferrucci L, Guralnik JM, Studenski S, et al; Interventions on Frailty Working Group. Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: a consensus report. J Am Geriatr Soc. 2004;52:625–634. 43. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59:255–263. 44. Abellan van Kan G, Rolland Y, Bergman H, et al. The I.A.N.A Task Force on frailty assessment of older people in clinical practice. J Nutr Health Aging. 2008;12:29–37. 45. de Vries NM, Staal JB, van Ravensberg CD, et al. Outcome instruments to measure frailty: a systematic review. Ageing Res Rev. 2011;10:104–114. 46. Fried LP, Tangen CM, Walston J, et al; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–M156. 47. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489–495. 48. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2002;57:M326–M332. 49. Cesari M, Penninx BW, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2004;59:242–248. 50. Leng SX, Xue QL, Tian J, et al. Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp Gerontol. 2009;44:511–516. 51. Michaud M, Balardy L, Moulis G, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14:877–882. 52. Barzilay JI, Blaum C, Moore T, et al. Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. Arch Intern Med. 2007;167:635–641. 53. Goulet ED, Hassaine A, Dionne IJ, et al. Frailty in the elderly is associated with insulin resistance of glucose metabolism in the postabsorptive state only in the presence of increased abdominal fat. Exp Gerontol. 2009;44:740–744. 54. Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women’s Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci. 2005;60:729–735. 55. Chin A Paw MJ, Dekker JM, Feskens EJ, et al. How to select a frail elderly population? A comparison of three working definitions. J Clin Epidemiol. 1999;52:1015–1021. 56. Dumurgier J, Elbaz A, Ducimetière P, et al. Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study. BMJ. 2009;339:b4460. 57. Klein BE, Klein R, Knudtson MD, et al. Frailty, morbidity and survival. Arch Gerontol Geriatr. 2005;41:141–149. 58. Newman AB, Gottdiener JS, Mcburnie MA, et al; Cardiovascular Health Study Research Group. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci. 2001;56:M158–M166. 59. Purser JL, Kuchibhatla MN, Fillenbaum GG, et al. Identifying frailty in hospitalized older adults with significant coronary artery disease. J Am Geriatr Soc. 2006;54:1674–1681.
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60. Ekerstad N, Swahn E, Janzon M, et al. Frailty is independently associated with short-term outcomes for elderly patients with non-ST-segment elevation myocardial infarction. Circulation. 2011;124:2397–2404. 61. Ekerstad N, Swahn E, Janzon M, et al. Frailty is independently associated with 1-year mortality for elderly patients with non-ST-segment elevation myocardial infarction. Eur J Prev Cardiol. 2014;21:1216–1224. 62. Singh M, Rihal CS, Lennon RJ, et al. Influence of frailty and health status on outcomes in patients with coronary disease undergoing percutaneous revascularization. Circ Cardiovasc Qual Outcomes. 2011;4:496–502.
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63. Hordijk-Trion M, Lenzen M, Wijns W, et al; EHS-CR Investigators. Patients enrolled in coronary intervention trials are not representative of patients in clinical practice: results from the Euro Heart Survey on Coronary Revascularization. Eur Heart J. 2006;27:671–678. 64. Gurwitz JH, Goldberg RJ, Chen Z, et al. Recent trends in hospital mortality of acute myocardial infarction–the Worcester Heart Attack Study. Have improvements been realized for all age groups? Arch Intern Med. 1994;154:2202–2208. 65. Sahyoun NR, Lentzner H, Hoyert D, Robinson KN. Trends in causes of death among the elderly. Aging Trends. 2001:1–10.
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Acute Coronary Syndrome Among Older Patients A Review Murugapathy Veerasamy, MBBS, MRCP,*† Richard Edwards, PhD,† Gary Ford, FRCP,* Tom Kirkwood, PhD,‡ Julia Newton, PhD, FRCP,*‡ Dave Jones, MD, FRCP,* and Vijay Kunadian, MBBS, MD, FRCP*†
Abstract: Ischemic heart disease is the leading cause of mortality worldwide. Due to advances in medicine in the past few decades, life expectancy has increased resulting in an aging population in developed and developing countries. Acute coronary syndrome causes greater morbidity and mortality in this group of older patients, which appears to be due to age-related comorbidities. This review examines the incidence and prevalence of acute coronary syndrome among older patients, examines current treatment strategies, and evaluates the predictors of adverse outcomes. In particular, the impact of frailty on outcomes and the need for frailty assessment in developing future research and management strategies among older patients are discussed.
and retrospective studies were included. Cross-references from the citation lists were examined and included for relevant material.
PREVALENCE OF ACS AMONG OLDER PATIENTS
schemic heart disease (IHD) is the leading cause of death worldwide.1 There is a steep increase in mortality due to IHD among those >70 years of age.2 There has been rapid progress in the management of acute coronary syndrome (ACS) over the past decade with the use of adjunctive pharmacotherapy, specifically novel antiplatelets and anticoagulants, and advanced percutaneous coronary intervention (PCI) procedures with drug-eluting stents becoming common place.3–6 These medical and technical advancements have led to improved survival and gains in life expectancy, especially in younger persons (75 years of age (n = 55,028) died from IHD compared to younger individuals 70 years represented 49% of patients with an MI in the MINAP data. The average age for a first STEMI was 65 years, while that of non-STEMI (NSTEMI) was 70 years (21% of STEMI patients and 26% of NSTEMI patients were between 70 and 79 years of age, in comparison to 15% of patients with STEMI and 27% of patients with NSTEMI who were 80–89 years of age). Although cases of STEMI appear to be equally distributed around the age-range 60–69 years, for NSTEMI the majority present older than this age.8 In the Global Registry of Acute Coronary Events (GRACE),9 increasing age was associated with increased incidence of NSTEMI. NSTEMI was diagnosed in >30% of patients aged 75 years). All in-hospital events after ACS were more frequent among elderly patients. Cardiogenic shock was nearly 6 times more common in the oldest compared with the youngest group (9.8% vs 1.6%, respectively). Rates of major bleeding were twice more in patients aged ≥85 years compared to 75 years were excluded from many trials that compared fibrinolysis against primary PCI on the basis of age.12 There is no clear consensus on the optimal reperfusion strategy to use in the elderly due to lack of clinical trial data and details of comorbidities.13 From subgroup analysis, primary PCI has better outcomes compared to fibrinolysis in older patients as seen in the Global Utilization of Streptokinase and Tissue Plasminogen Activator (TPA) for Occluded Coronary Arteries (GUSTO) IIb trial in which approximately 15% were >75 years.14
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TABLE 1. Reperfusion Strategy in Older Patients With STEMI Study De Boer et al15 PPCI versus Thrombolysis Goldenberg et al16 PPCI versus Thrombolysis
Age Group
Number of Patients
>75 years
87
≥70 years
130
Bueno et al17 TRIANA trial PPCI versus thrombolysis
≥75 years
266
GRACE Registry subgroup18 PPCI versus Thrombolysis
≥70 years
1134
70–80 years and >80 years
6763
De Boer et al19 Meta-analysis PPCI versus Thrombolysis
Outcomes Composite of death, MI and stroke at 30 days: 9% vs 29% P = 0.01; at 1 year: 13% vs 44% P = 0.001 Combined end point of death, reinfarction, or revascularization for recurrent ischemia 29% vs 93%, P < 0.01 Significant reduction in the rates of the composite end points of death, reinfarction, or disabling stroke with PPCI, OR 0.64, 95% CI 0.45–0.91, P = 0.013 In-hospital complications: mortality 13.5% vs 14.8%, reinfarction 1.1% vs 5.7%, cardiogenic shock 11.3% vs 11.6%, major bleeding 8.6% vs 5.9%, and stroke 1.1% vs 2.8% 30-day mortality, MI, or stroke; 70–80 years: 12.5% vs 24.2, OR 0.45, 95% CI: 0.34–0.59; >80 years: 23.3 vs 35.1, OR 0.56, 95% CI: 0.36–0.86
CI indicates confidence interval; GRACE, Global Registry of Acute Coronary Events; MI, myocardial infarction; OR, odds ratio; PPCI, primary percutaneous coronary intervention.
Few studies have been conducted specifically for elderly patients with STEMI. In a study by de Boer et al,15 87 patients >75 years old with acute MI were assigned to PCI or thrombolysis with intravenous streptokinase. There was a significant increase in the incidence of death, reinfarction, and stroke at 30 days [29% vs 9%, relative risk (RR): 4.3, 95% confidence interval (CI) 1.2–20.0, P = 0.01) and 1 year (44% vs 13%, RR: 5.2; 95% CI 1.7–18.1, P = 0.001) in the thrombolysis group compared with the PCI group. Goldenberg et al16 compared 130 consecutive ≥70 years old patients with STEMI after assigning them to receive either primary PCI or thrombolysis with TPA. At 6 months, patients treated with primary PCI, compared with those treated with thrombolytic therapy, had a trend toward lower incidence of reinfarction (2% vs 14%, P = 0.053), and significant reductions in the rates of revascularization for recurrent ischemia (9% vs 61%, P < 0.001) and in the combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < 0.01). Rates of major bleeding were also significantly reduced in the group receiving primary PCI (0% vs 17%, P = 0.03). In the TRatamiento del Infarto Agundo de miocardion eN Ancianos (TRIANA) study,17 a randomized, controlled trial involving 266 patients >75 years of age (mean age 81), patients received either primary PCI (n = 134) or fibrinolysis (n = 132). In this trial, which was ceased prematurely due to difficulties in recruitment, the rates of the composite trial end point of all-cause mortality, reinfarction, or stroke were lower in the group receiving primary PCI compared to those receiving fibrinolysis, but statistical significance was not reached (OR 0.69, 95% CI 0.38–1.23, P = 0.21). In a pooled analysis, primary PCI compared with thrombolysis demonstrated no overall mortality reduction among patients receiving primary PCI compared to those receiving fibrinolysis (OR 0.74, 95% CI 0.49–1.13, P = 0.16). However, there was a significant reduction in the rates of the composite end points of death, reinfarction, or disabling stroke with primary PCI (OR 0.64, 95% CI 0.45–0.91, P = 0.013). The GRACE registry demonstrated lower adjusted in-hospital mortality (OR 0.62; 95% CI 0.39–0.96) for primary PCI compared with fibrinolysis among 2975 patients with STEMI who were aged ≥70 years.18 In a meta-analysis of 22 randomized, controlled trials (n = 6763), 30-day mortality increased with increasing age and ranged from 1.1% in the fibrinolysis group and 1.8% in the primary PCI group in patients ≤50 years, to 26.4% and 18.3% in patients >80 years of age. In this analysis of randomized trials,19 the reduction in clinical end points of death, MI, and stroke by primary PCI was not influenced by age. In octogenarians who comprised 6% of the patients in © 2014 Lippincott Williams & Wilkins
the meta-analysis, those who were randomized to primary PCI had a lower incidence of mortality (18.3% vs 26.4% events; P = 0.049) than their counterparts who were randomized to fibrinolysis. However, there was no difference in the occurrence of repeat MI (3.9% vs 7.0%; P = 0.18) and stroke (5.8% vs 7.9%; P = 0.45).19 These studies suggest that among older patients presenting with STEMI, primary PCI is the optimal revascularization strategy.
Revascularization Strategy in NSTEMI In the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18 (TACTICS-TIMI 18) study,20 patients aged >65 years who were treated with an early invasive approach of catheterization within 4–48 hours and revascularization if appropriate had a lower risk of death, subsequent MI, or rehospitalization for ACS at 6 months than patients who underwent a conservative strategy of revascularization only with objective evidence of ischemia (14.9% vs 17.8%, respectively). However, this was not statistically significant.20 From the CRUSADE Quality Improvement Initiative,21 the unadjusted incidence of in-hospital mortality for all patients (n = 17926) was 2.0% for patients who underwent early invasive management within 48 hours compared with 6.2% for patients who did not undergo early invasive management [adjusted hazard ratio (HR): 0.63, 95% CI 0.52–0.77]. In this study, younger and healthier patients generally received the benefit of early invasive management, whereas older patients with more comorbidities and a greater likelihood to benefit from invasive treatment for NSTEMI were more likely to be managed conservatively.21 In the Acute Coronary Syndromes Registry study,22 1936 patients ≥75 years with NSTEMI were included and analyzed by 2 groups. One thousand five patients underwent coronary angiography and revascularization if indicated, and 931 patients received conservative treatment. The mean age was 78.7 years versus 82.2 years (P < 0.0001) and women comprised 48.3% versus 58.6% (P < 0.0001) of each group, respectively. In-hospital mortality and the combined end point of death or non-fatal reinfarction were lower in the patients undergoing invasive management compared with the group managed by conservative strategy (6.0% vs 12.5%, P < 0.0001 and 9.6% vs 17.3%, P < 0.0001, respectively). There was a significant reduction in 1-year mortality in the invasive treatment group compared to the conservative treatment group (OR 0.56, 95% CI 0.38–0.81).22 In a recent study comparing the different management strategies used among patients >75 years of age between 2 different www.cardiologyinreview.com | 27
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cities (Goteborg [Sweden] and Minneapolis St Paul [USA]), it was observed that in Goteborg a smaller proportion of patients received PCI (7.3% vs 32.8%; P < 0.0001 among men, 6.6% vs 29.4%; P < 0.0001 among women).23 Subsequently, survival after 7.5 years follow-up was observed to be lower in Goteborg (17.5% vs 26.6%, [OR for survival at follow-up: 0.66, 95% CI: 0.50–0.88] among men and 17.0% vs 28.8% [OR 0.49, 95% CI 0.36–0.67] among women). While the increased survival rate was thought to be attributable, at least in part, to the increased utilization of PCI in the Minneapolis cohort, it should be noted that several other factors could have contributed, such as differences in medical management and other geographical variables.23 In the Italian Elderly ACS study, 313 non-ST elevation ACS patients ≥75 years old were randomized to an early aggressive approach or initial conservative approach.24 In the early aggressive treatment group, 88% of patients underwent coronary angiography and 55% had PCI, and in the initial conservative group it was 29% and 23%, respectively. There was a significant reduction in the primary end point (death, MI, stroke, and rehospitalization for cardiovascular causes) in the early aggressive treatment group with raised troponin on admission compared to conservative approach at 1 year (HR 0.43; 95% CI 0.23–0.80, log rank P < 0.05), while there was no difference noted between the 2 groups with normal troponin on admission. Overall, these studies suggest that there may be better outcomes with an early invasive management strategy in the elderly population in carefully selected patients presenting with NSTEMI compared with conservative medical therapy.
PCI Versus Coronary Artery Bypass Grafting Older patients are more likely than younger patients to have 3-vessel disease.25 In a retrospective study of 10,141 ACS patients with multivessel disease who were ≥85 years (mean age 87.2 years), patients were followed up for 3 years after either coronary artery bypass grafting (CABG) or multivessel PCI. Although lower survival was noted in the early months after CABG compared to PCI (OR 1.48, 95% CI 1.34–1.64, P < 0.01), CABG provided significantly better survival (OR 0.60, 95% CI 0.53–0.69, P < 0.05) and freedom from the composite outcome of death, repeat revascularization, stroke, and acute MI at 36 months (OR 0.83, 95% CI 0.76–0.91, P < 0.01).26 Long-term outcomes were poor in patients with heart failure, lung disease, and peripheral vascular disease in the CABG group. In a meta-analysis of 10 randomized, controlled trials by Flather et al,25 over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age. CABG led to an increased risk of mortality among patients in the lowest tertile for age (n = 2602, mean age 49.8), with adjusted CABG to PCI HR of 1.23 (95% CI 0.95–1.59). However, in the middle tertile (n = 2602, mean age 61.0), the HR was 0.89 (95% CI 0.73–1.10), favoring CABG. In the oldest tertile (n = 2602, mean age 70.5), the HR decreases further to 0.79 (95% CI 0.67–0.94). It was observed that above 59 years of age, the HR fell to 75 years of age is lacking.
DOES THE POPULATION STUDIED REFLECT THE POPULATION TREATED? Evidence from clinical trials to inform the management of ACS in older patients is limited. More than half of all trials for coronary disease in the past decade failed to enroll patients >75 years of age, with this subgroup accounting for just 9% of all patients enrolled in trials.30 Analysis from the CRUSADE Quality Improvement Initiative demonstrated that among a community population with non-ST-elevation ACS, patients who were enrolled in a clinical trial (2.5% of the overall CRUSADE population) were younger (median 65 vs 68 years), more often male (67.9% vs 59.3%), had less renal insufficiency (8.5% vs 13.5%), and had less heart failure (13.2% vs 19.0%) than those not enrolled in trials.31 Evidence-based recommendations from trials do not account for the age-related differences in physiology and disease that may alter these relationships. The age gap between trials and community populations begins at age 75 years and widens with age.32 Even the older patients included in trials are different from the older patients in the community. Trial populations have lower rates of traditional cardiovascular risk factors, less comorbidity, and better renal function in each age subgroup than do community populations.31 As older patients are at increased risk from cardiac events, the absolute benefit of treatment should increase if treatment risks can be balanced against benefits.33 Risks and benefits derived from trials cannot always be extrapolated to older patients in daily clinical practice due to the differences between the patient groups.34 The current evidence in the management of older ACS patients is limited due to the less number of older patients in the randomized trials.
PREDICTORS OF POOR OUTCOMES IN OLDER ACS PATIENTS Age Adverse events following ACS increase with age.11,19,35–37 RR of in-hospital death among ACS patients increased by 70% on average for each 10-year increase in age (OR 1.70, 95% CI, 1.52–1.82).37 This association remains even after accounting for confounding factors, such as heart rate, systolic blood pressure, serum creatinine, electrocardiographic changes, cardiac arrest, and history of diabetes or hypertension.
Comorbidities The decision to intervene in older ACS patients need to be balanced against the general health and comorbidities of these patients.34 Old age is not an isolated risk factor especially when age-associated conditions, such as anemia, kidney disease, frailty, disability, and cognitive dysfunction, have an impact on the outcomes of ACS management. In addition, diminished organ reserves and abnormal functional and cognitive status influence the nature of disease presentation, response to treatment, and recovery.32 Renal dysfunction is © 2014 Lippincott Williams & Wilkins
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associated with an increased risk of bleeding in older populations.38 Old age-related functional and cognitive changes have an impact on disease-related risks, which needs to be assessed in the management of older ACS patients.
Frailty Declining physiological reserve and resulting impaired resistance to stressors lead to frailty syndrome.39 Twenty-five to 50% of patients with cardiovascular disease can be identified as frail, depending on the frailty scale used and the population group studied.40 The cause for decline in physiological reserve is multifactorial and involves multiple organ systems. Frailty has become increasingly relevant in the field of cardiovascular medicine as the patient population is aging, and also there is increasing evidence of the association between cardiovascular disease and frailty, both at the mechanistic level and the epidemiologic level.41 Activities of daily living (ADL), physiological reserves, nutritional status (albumin, weight loss), and functional status are all important markers of older patients at increased risk of morbidity and mortality.42 Altered cognition, hearing, and vision may delay presentation and result in increased risks due to delays in commencing interventional treatment. Impaired communication affects decision making, and these patients would find it difficult to adhere to a treatment plan and consent for invasive procedures. As frailty includes a number of components, a better understanding of age-related health issues separate from diseaserelated risk is needed.43 Frailty is not reflected by disabilities in ADL (eg, getting dressed unassisted) or instrumental ADL (such as going shopping unassisted) alone. Frailty occurs earlier than disability and can be elicited in a large number of well-functioning older adults. Disability can be viewed as the end-result of long-standing frailty and comorbidity burden.40 Although there is a overlap between frailty, disability, and comorbid conditions, these represent distinct domains.43 Frailty can be assessed by a number of clinical instruments and scores.44,45 The variables measured include physical inactivity, strength, exhaustion, comorbid conditions, and cognitive impairment as main components. A task force on frailty assessment in older people suggested that gait speed could represent the most suitable instrument to be implemented in both research and clinical evaluation of older people to assess frailty.44 The 5-minute gait speed test is a simple and effective way of objectively measuring frailty in patients with cardiovascular disease and should be incorporated in risk assessment. Fried et al46 used data from the Cardiovascular Health Study to develop a tool for the assessment of frailty among adults aged ≥65 years. Participants (n = 5317) ≥65 years were assessed annually. Examinations and surveillance were conducted assessing the presence of incident disease, hospitalization, falls, disability, and mortality. Frailty was defined as “a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 pounds in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity.” According to the above criteria, 6.9% of the study population were frail. The prevalence increased with increasing age and was greater in women than in men. Over a 3-year period, frailty was independently associated with increased falling incidents, worsening mobility, disability in ADL, hospitalization, and mortality. The presence of 1 or 2 of the Fried frailty criteria indicating intermediate frail status showed an intermediate risk of these outcomes and an elevated risk of becoming frail over a period of 3 to 4 years. Rockwood et al47 developed the 7-point Clinical Frailty Scale (category 1: very fit—robust, active, energetic, well motivated, and fit; these people commonly exercise regularly and are in the most fit group for their age to category 7: severely frail—completely © 2014 Lippincott Williams & Wilkins
Coronary Disease in Older Patients
dependent on others for their ADL, or terminally ill) and used it to measure frailty in 2305 elderly patients participating in the Canadian Study of Health and Aging. After adjustment for age, sex, and education, each 1-category increment of the clinical frailty scale significantly increased the risks of death (21.2%, 95% CI 12.5–30.6%) and entry into an institution (23.9%, 95% CI 8.8–41.2%) within 6 years.
Markers Associated With Frailty Chronic low-grade inflammation plays a common role in pathways leading to cardiovascular disease and frailty. Circulating inflammatory markers such as neutrophils, monocytes, high sensitivity C-reactive protein, and interleukin-6 are increased in cardiovascular disease and frailty.48–51 Another common pathway in the development of cardiovascular and frailty is insulin resistance. Independent of its contribution to chronic inflammation, insulin resistance leads to impaired muscle protein breakdown, which in turn leads to reduced availability of amino acids for maintenance and repair functions.52,53
Frailty and Poor Cardiovascular Outcomes Frail patients with cardiovascular disease, especially those undergoing invasive procedures or experiencing coronary artery disease and heart failure, are more likely to experience major cardiovascular events and death compared to their non-frail counterparts.40 Several studies have demonstrated an association between frailty and cardiovascular disease in community-dwelling older adults.54–59 The prevalence of frailty in older patients with cardiovascular disease is displayed in Table 2. Frailty is a powerful predictor of adverse cardiovascular outcomes and hence, frailty measures should be routinely used in cardiovascular risk assessment. This is especially important in the management of ACS.
Frailty in the Setting of NSTEMI In a study of 307 hospitalized NSTEMI patients ≥75 years of age, 149 (48.5%) were considered frail by the 7-point frailty criteria of Rockwood et al.47 A lesser number of frail patients underwent coronary angiography compared to non-frail patients. Frailty was independently associated with the risk of major adverse cardiovascular (death from any cause, myocardial reinfarction, revascularization due to ischemia, hospitalization for any cause, major bleeding, stroke/transient ischemic attack, and need for dialysis) outcomes (OR 2.2; 95% CI 1.3–3.7), in-hospital mortality (OR 4.6; 95% CI 1.3–16.8), and 1-month mortality (OR 4.7; 95% CI, 1.7–13.0). From this study, Ekerstad et al60 concluded that frailty was strongly and independently associated with in-hospital mortality, 1-month mortality, and prolonged hospital care. Similarly, in the 1-year follow-up of this study, there was increased mortality in frail patients compared with non-frail patients (HR 4.3, 95% CI 2.4–7.8).61
Frailty in Patients Undergoing PCI In a prospective cohort study by Singh et al,62 frailty (as defined by the frailty score by Fried et al46) was added to conventional cardiovascular risk factors in the Mayo Clinic Risk Score. Frailty was associated with increased long-term mortality or MI (HR 2.45; 95% CI 1.33–4.53) among patients undergoing PCI. The authors concluded that the addition of frailty, comorbidity, and quality of life significantly improves the prognostic ability of the Mayo Clinic Risk score.62
FUTURE DIRECTIONS Limited clinical randomized controlled trial data to guide acute care in older patients and the uncertainty about risk-benefit assessment with advanced age is likely to explain the underuse of appropriate medications and invasive treatment strategies.30 Older patients who are at high risk of adverse outcomes following ACS are underrepresented in clinical trials, despite the fact that older patients constitute www.cardiologyinreview.com | 29
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TABLE 2. Prevalence of Frailty in Older Patients With CVD Design
Number of Patients
Women’s Health and Aging Studies I and II (WHAS I and II)54 Zutphen Elderly Men’s Study55 French 3 city Study56
Study
Secondary analysis
670
Frailty (Fried), prevalent CVD, 3-year mortality
Key Variables
Community dwellers
Population
OR 2.72 (95% CI 1.72–4.30)
Secondary analysis
450
Community dwellers
OR 4.1 (95% CI 1.8–9.3)
Prospective cohort
3208
Community dwellers
Beaver Dam Eye Study57
Secondary analysis
2962
Cardiovascular Health Study (CHS)58
Secondary analysis
4735
OR 3.00 (95% CI 1.65–5.57) OR 2.67 (95% CI 1.33–5.41) OR 2.79 (95% CI 2.12–3.67)
Purser et al59
Prospective cohort
309
Frailty (Chin), prevalent CVD, 3-year mortality Gait speed, CVD events and mortality Frailty (Klein), prevalent CVD, 10-year mortality Frailty (Fried), prevalent CVD, subclinical CVD, 7-year mortality Frailty (Fried, Rockwood, gait velocity), 6-month mortality
Community dwellers Community dwellers In-patients with severe coronary artery disease
Frailty, CVD, Mortality
OR 4.0 (95% CI 1.1–13.8)
CI indicates confidence interval; CVD, cardiovascular disease; OR, odds ratio.
a significant proportion of the patient population and are more likely to benefit from treatment strategies due to higher risk.32,63 For gains in quality life-years following ACS to continue, survival from acute heart disease will need to also extend to the very older population.64,65 It is important to understand the risks and benefits of treatment in this group to improve outcomes. Frailty assessment might usefully be incorporated into the management of older patients with ACS. Future large-scale randomized studies evaluating novel therapies in addition to contemporary care are required for the aging patients presenting with ACS. A study is currently underway consisting of older patients presenting with ACS and undergoing PCI to evaluate predictors of poor quality of life and adverse outcomes following PCI and to develop an integrated risk score to predict outcomes and inform clinical decision making (UKCRN ID 12742, NCT 01933581).
CONCLUSION Older patients constitute a significant group of ACS patients. With increasing life expectancy and advances in medicine, the proportion of older patients presenting with ACS will increase. The older high-risk patients who are likely to benefit most from current pharmacotherapy and invasive procedures for ACS are managed conservatively due to the difficulty in risk-benefit assessment. This is a result of a lack of clear evidence due to underrepresentation of this older group in clinical trials. It is important to recognize that chronological age does not always reflect biological age. Frailty, functional status, and social aspects are not routinely assessed in older ACS patients. Future trials should enroll a greater proportion of older patients to reflect the real world population needing treatment and assess and report frailty status of trial participants. Standard reporting of age groups across trials and registries is needed to facilitate comparisons and pooling of data. A better understanding and phenotyping of older patients presenting with ACS are required. Prospective trials performed exclusively in the older patients will be of help in assessing the benefits and safety of pharmacotherapy and invasive procedures. ACKNOWLEDGMENT This research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. 30 | www.cardiologyinreview.com
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