Management and 6-month outcomes in elderly and very elderly patients with high-risk non-ST-elevation acute coronary syndromes: The Global Registry of Acute Coronary Events

Abstract

Aims

To test the hypothesis that increasing age in patients presenting with high-risk non-ST-segment elevation acute coronary syndromes (NSTE-ACS) does not adversely influence the benefit of an early invasive strategy on major adverse events at 6 months.

Methods and results

We report clinical outcomes in young (<70), elderly (70–80), and very elderly (>80 years) patients with high-risk NSTE-ACS enrolled in GRACE between 1999 and 2006. Six month data were available in 18 466 patients (27% elderly, 16% very elderly). Elderly and very elderly patients were less likely to receive evidence-based treatments at discharge and had a longer hospital stay (6 vs. 5 days). Angiography was performed more frequently in younger patients (67 vs. 33% in very elderly, 55% in elderly; P < 0.0001). Multiple logistic regression analysis confirmed the benefit of revascularization on the primary study endpoint (6-month stroke, death, myocardial infarction) in young [odds ratio (OR) 0.69, 95% confidence interval (CI) 0.56–0.86], elderly (0.60, 0.47–0.76), and very elderly (0.72, 0.54–0.95) patients. Revascularization was associated with reductions in 6-month mortality (OR 0.52, 95% CI 0.37–0.72 in young; 0.38, 0.26–0.54 in elderly; 0.68, 0.49–0.95 in very elderly). Stroke risk in hospital or at 6 months was not increased by revascularization.

Conclusion

Following presentation with high-risk NSTE-ACS, an evidence-based approach to management was noted less frequently with advancing patient age. Angiography, in particular, was less likely to be undertaken. Revascularization, however, when performed, was associated with significant benefits at 6 months, independent of age, and did not increase risk of stroke.

Acute coronary syndrome, Revascularization, Elderly

Introduction

The management of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) has changed dramatically in recent years. In patients who are regarded as high risk, based predominately on troponin status with or without electrocardiographic changes, guidelines^1–3 recommend further risk stratification with early angiography and subsequent revascularization, if considered appropriate. Elderly patients, who are frequently under-represented in clinical trials, constitute a significant proportion of this patient population, with advanced age considered an independent risk factor for early morbidity and mortality following presentation for NSTE-ACS.⁴ Poorer outcome is influenced not only by extensive coronary artery disease but also by more complex co-morbidities.⁵ In addition, elderly patients are considered more likely than younger patients to suffer complications following revascularization procedures.⁶

This potential for increased complications may result in a reluctance to undertake revascularization procedures in older patients, as demonstrated in an earlier study from the Global Registry of Acute Coronary Events (GRACE).⁷ Published registry data and subgroup analysis of randomized control trials contradict this concern and suggest that elderly patients with high-risk NSTE-ACS have a better outcome when they undergo early revascularization compared with those managed conservatively.^8–10 A paucity of longer term data exists in the real-world setting; thus the optimal management strategy for elderly patients with ACS remains the subject of debate. The objective of this study was to test the hypothesis that increasing age in patients presenting with high-risk NSTE-ACS does not adversely influence the benefit of an early invasive strategy on major adverse events at 6 months.

Methods

Full details of the GRACE methods have been published elsewhere.^11–13 GRACE is designed to reflect an unselected population of patients with ACS, irrespective of geographical region. A total of 113 hospitals located in 14 countries in North and South America, Europe, Australia, and New Zealand have contributed data to this observational study. Data from 104 sites in 14 countries were used for this analysis.

Adult patients (≥18 years old) admitted with a presumptive diagnosis of ACS at participating hospitals were potentially eligible for this study. Eligibility criteria were a clinical history of ACS accompanied by at least one of the following: electrocardiographic changes consistent with ACS, serial increases in biochemical markers of cardiac necrosis (CK-MB, creatine phosphokinase, or troponin), and documented coronary artery disease. Patients with non-cardiovascular causes for the clinical presentation, such as trauma, surgery, or aortic aneurism, were excluded. Patients were followed up at ∼6 months by telephone, clinic visits, or through calls to their primary care physician to ascertain the occurrence of several long-term outcomes. For hospital survivors, a standardized follow-up form was completed during a telephone call to the patient, next of kin, and/or caregiver at a targeted interval of 6 months from discharge to telephone call. The data forms were forwarded to the international coordinating centre where, following a review of case records for completeness and face validity, the data were entered by scanning the forms directly into the database. Where required, study investigators received approval from their local hospital ethics or institutional review board for the conduct of this study.

To enrol an unselected population of patients with ACS, sites were encouraged to recruit the first 10–20 consecutive eligible patients each month. Regular audits are performed at all participating hospitals. Data were collected by trained study coordinators using standardized case report forms. Demographic characteristics, medical history, presenting symptoms, duration of pre-hospital delay, biochemical and electrocardiographic findings, treatment practices, and a variety of hospital outcome data were collected. Standardized definitions of all patient-related variables, clinical diagnoses, and hospital complications and outcomes were used. All cases were assigned to one of the following categories: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina.

Patients were diagnosed with STEMI when they had new or presumed new ST-segment elevation ≥1 mm seen in any location, or new left bundle-branch block on the index or subsequent ECG with at least one positive cardiac biochemical marker of necrosis (including troponin measurements, whether qualitative or quantitative). In cases of NSTEMI, at least one positive cardiac biochemical marker of necrosis without new ST-segment elevation seen on the index or subsequent ECG had to be present. Unstable angina was diagnosed when serum biochemical markers indicative of myocardial necrosis in each hospital's laboratory were within the normal range. Full definitions can be found on the GRACE web site at www.outcomes.org/grace. Hospital-specific feedback regarding patient characteristics, presentation, management, and outcomes is provided to each centre on a quarterly basis in the form of written reports.

Patients with high-risk NSTE-ACS were included in the analysis for this study. High risk was defined as the presence of dynamic ST-segment changes and/or a positive troponin assay (or other cardiac markers). Patients were then divided into three groups to facilitate comparison across age strata: <70 years (young); 70–80 years (elderly); and >80 years (very elderly).

Hospital management and 6-month outcomes were compared between groups to assess the potential benefit of revascularization. The primary study endpoints were stroke (defined as an acute neurological deficit that lasted for >24 h), death, or recurrent myocardial infarction in hospital and within 6 months of discharge.

Statistical analysis

The statistical analysis was performed with SAS v9.1 (SAS Institute, Cary, NC, USA). Categorical variables were analysed using the χ² test or Fisher's exact test. Continuous variables were analysed using the Wilcoxon rank-sum test for two-comparison groups and the Kruskal–Wallis test for three-comparison groups.

Multiple logistic regression analysis was used to evaluate the effect of early invasive treatment on hospital mortality and 6-month outcomes, and to assess the interaction between age group and invasive treatment. The variables included in the model were age; medical history [smoker, angina, myocardial infarction, heart failure, coronary intervention, percutaneous coronary intervention, coronary artery bypass grafting (CABG), diabetes, hypertension, hyperlipidaemia, renal insufficiency]; Killip class; inhospital events (recurrent ischaemic symptoms, congestive heart failure or pulmonary oedema, cardiogenic shock, cardiac arrest or ventricular fibrillation, atrial fibrillation or flutter, sustained ventricular tachycardia, non-CABG-related major bleeding); and the GRACE risk score. For testing the interaction between age group and treatment, the effect of an invasive strategy on 6-month outcomes was considered statistically significantly different at P < 0.05.

Results

Patient population

A total of 35 512 patients with a discharge diagnosis of NSTE-ACS were enrolled in GRACE between April 1999 and August 2006. Of these, 23 595 were considered high risk; 6-month outcome data were available in 18 466, who constitute the study population. Nearly half of the patients (44%) were older than 70 years, with 27% considered elderly and 16% very elderly. The main baseline characteristics of the three groups are given in Table 1.

Table 1

Baseline characteristics for high-risk patients with NSTE-ACS

	<70 years (n = 10 380)	70–80 years (n = 5057)	>80 years (n = 3029)	P-value
Demographic
Mean age, years	57 ± 8.7	75 ± 2.9	85 ± 4.1	<0.0001
Men, n (%)	7677 (74)	3009 (60)	1433 (48)	<0.0001
Cardiovascular risk factor, n (%)
Current/past smoker	6986 (68)	2438 (49)	1074 (36)	<0.0001
Prior angina	5651 (55)	3070 (61)	1722 (57)	<0.0001
Prior myocardial infarction	3068 (30)	1837 (37)	1220 (41)	<0.0001
Prior heart failure	747 (7.2)	804 (16)	813 (27)	<0.0001
Previous coronary angiography diagnostic for ischaemic heart disease	3208 (32)	1796 (36)	955 (32)	<0.0001
Previous PCI	1854 (18)	832 (17)	452 (15)	<0.001
Previous CABG	1302 (13)	958 (19)	471 (16)	<0.0001
Diabetes	2641 (26)	1597 (32)	769 (26)	<0.0001
Hypertension	6075 (59)	3598 (72)	2198 (73)	<0.0001
Severe renal failure (GFR < 30 mL/min)	388 (4.0)	322 (6.7)	320 (11)	<0.0001
Hyperlipidaemia	5465 (53)	2515 (50)	1175 (39)	<0.0001
Atrial fibrillation	452 (4.4)	677 (14)	576 (19)	<0.0001
Killip class I on presentation, n (%)	9051 (89)	3839 (78)	2017 (68)	<0.0001
Elevated cardiac markers, n (%)	7675 (74)	3798 (76)	2481 (82)	<0.0001
Dynamic ST-segment changes, n (%)	5250 (51)	2783 (55)	1565 (52)	<0.0001
GRACE risk score, median (q1, q3)	113 (95, 103)	145 (129, 164)	166 (148, 186)	<0.001

GFR, glomerular filtration rate.

Young and elderly patients were more likely to be men (74 and 60%, respectively); very elderly patients were more often women (53%). Hypertension and diabetes were more common in the elderly groups. Younger patients were much more likely to be current or past smokers. At least one-third of all patients had previously undergone coronary revascularization. Heart failure was more likely to complicate presentation with advancing age and was noted in one in four very elderly patients. Severe renal failure (estimated glomerular filtration rate < 30 mL/min) was more common with advancing patient-years. Elderly patients were more likely to have both elevated cardiac markers and dynamic ECG changes indicative of increased risk. In addition, the GRACE risk score¹⁴ increased with advancing age.

Inhospital management

The rates of use of aspirin and beta-blockers were high in all three cohorts (Table 2). Statins were used less frequently in older patients and calcium-channel blockers more frequently. Overall, glycoprotein IIb/IIIa receptor blockers were used infrequently in this high-risk NSTE-ACS population, and were less likely to be used with advancing patient age. Thienopyridines were prescribed less commonly in older patients. Warfarin usage was highest in the elderly. This may in part relate to more frequent rate of atrial fibrillation with advancing age. Angiography was undertaken in two-thirds of younger patients and one-third of very elderly patients. Revascularization procedures were less frequent among the older groups. Once angiography was performed, 63% of very elderly, 64% of elderly, and 67% of younger patients proceeded to revascularization. The median length of hospital stay was prolonged by 1 day in the elderly and very elderly groups.

Table 2

Inhospital management for high-risk patients with NSTE-ACS

	<70 years (n = 10 380)	70–80 years (n = 5057)	>80 years (n = 3029)	P-value
Aspirin, n (%)	9838 (95)	4647 (92)	2739 (91)	<0.0001
Beta-blocker, n (%)	9021 (87)	4086 (81)	2404 (80)	<0.0001
Statin, n (%)	7196 (70)	3095 (61)	1552 (52)	<0.0001
ACE-inhibitor/ARB, n (%)	6263 (61)	3284 (65)	1843 (61)	<0.0001
LMWH, n (%)	6441 (63)	3175 (63)	1721 (57)	<0.0001
Glycoprotein IIb/IIIa blocker, n (%)	3010 (29)	1102 (22)	441 (15)	<0.0001
Thienopyridine, n (%)	5525 (54)	2320 (46)	1163 (39)	<0.0001
Warfarin, n (%)	465 (4.6)	499 (10)	270 (9.1)	<0.0001
Nitrate, n (%)	8604 (83)	4274 (85)	2539 (84)	0.03
Calcium-channel blocker, n (%)	2375 (23)	1575 (32)	1005 (34)	<0.0001
Cardiac catheterization, n (%)	6926 (67)	2758 (55)	988 (33)	<0.0001
PCI, n (%)	3924 (38)	1402 (28)	535 (18)	<0.0001
CABG, n (%)	732 (7.2)	363 (7.3)	92 (3.1)	<0.0001
Length of stay (days)
Mean ± standard deviation	7.0 ± 6.7	8.2 ± 7.7	7.5 ± 6.8	<0.0001
Median (q1, q3)	5.0 (3, 9)	6.0 (4, 10)	6.0 (4.0, 9.0)

Inhospital outcomes

Recurrent ischaemic symptoms following admission were more common in patients undergoing revascularization (Table 3). Heart failure was noted less frequently in young and elderly patients treated with revascularization but not in the very elderly group. Major bleeding complications were statistically more likely in young and very elderly patients undergoing revascularization procedures, but not in the elderly cohort. No increase was noted in the incidence of stroke before hospital discharge in patients undergoing revascularization, regardless of age. Inhospital mortality was more likely to occur in older patients. A favourable inhospital mortality difference was noted in all cohorts undergoing revascularization.

Table 3

Inhospital events for high-risk patients with NSTE-ACS

	<70 years (n = 10 380)		70–80 years (n = 5057)		>80 years (n = 3029)
	With PCI/CABG 45% (n = 4612)	Without PCI/CABG 55% (n = 5694)	With PCI/CABG 35% (n = 1741)	Without PCI/CABG 65% (n = 3291)	With PCI/CABG 21% (n = 620)	Without PCI/CABG 79% (n = 2390)
CHF/pulmonary oedema, n (%)	316 (6.9)	488 (8.6), P < 0.01	243 (14)	623 (19), P < 0.0001	124 (20)	539 (23), P = 0.2
Recurrent ischaemia, n (%)	1169 (26)	1311 (23), P < 0.01	533 (31)	775 (24), P < 0.0001	182 (29)	511 (22), P < 0.0001
Major bleeding, n (%)	102 (2.2)	73 (1.3), P < 0.001	57 (3.3)	89 (2.7), P = 0.25	43 (7.0)	80 (3.4), P < 0.0001
Stroke, n (%)	21 (0.4)	20 (0.4), P = 0.6	22 (0.7)	16 (0.9), P = 0.3	3 (0.9)	21 (0.5), P = 0.45
Death, n (%)	87 (1.6)	203 (2.9), P < 0.001	95 (4.3)	262 (6.2), P < 0.001	57 (7.0)	363 (11), P < 0.001

CHF, congestive heart failure.

Six-month outcomes

At 6 months, rates of death, myocardial infarction, and stroke were more frequently noted with advancing age (Table 4). The combined triple endpoint was reduced in all patient cohorts by the use of revascularization (Table 4; Figure 1). This benefit remained evident after multivariable analysis testing for the interaction of age as a continuous variable and an invasive strategy (Table 5). A mortality benefit was noted in all groups. Risk of stroke was not increased in the elderly and very elderly groups undergoing revascularization. Re-admissions at 6 months for a suspected cardiac illness were more common in the very elderly group. The re-admission rate was reduced in elderly patients who underwent revascularization, with a non-statistically significant difference among the young and very elderly groups (Figure 1).

Figure 1

Six-month post-discharge outcomes in (A) young, (B) elderly, and (C) very elderly age groups according to those who did and did not undergo revascularization

Table 4

Six-month outcomes for high-risk patients with NSTE-ACS

	<70 years (n = 10 380)		70–80 years (n = 5057)		>80 years (n = 3029)
	With PCI/CABG 45% (n = 4612)	Without PCI/CABG 55% (n = 5694)	With PCI/CABG 35% ( n = 1741)	Without PCI/CABG 65% (n = 3291)	With PCI/CABG 21% (n = 620)	Without PCI/CABG 79% (n = 2390)
Death, n (%)	74 (1.7)	191 (3.5), P < 0.0001	50 (3.0)	268 (8.5), P < 0.0001	69 (12)	420 (19), P < 0.0001
Myocardial infarction, n (%)	85 (2.2)	128 (2.9), P = 0.06	51 (3.5)	141 (5.4), P < 0.01	27 (5.2)	146 (8.1), P = 0.03
Stroke, n (%)	18 (0.4)	46 (0.9), P < 0.01	27 (1.7)	39 (1.3), P = 0.30	12 (2.2)	62 (3.1), P = 0.24
Triple endpoint, n (%)	170 (3.8)	337 (6.2), P < 0.0001	118 (7.0)	415 (13), P < 0.0001	98 (17)	564 (25), P < 0.0001
Re-admission for cardiac event, n (%)	695 (17)	842 (16), P = 0.7	275 (17)	647 (22), P < 0.01	128 (23)	531 (26), P = 0.1

Table 5

Age-specific results from multiple logistic regression (adjusting for baseline characteristics, GRACE risk score, and in-hospital events)^a to evaluate the effect of an invasive strategy on 6-month post-discharge outcomes

	<70 years		70–80 years		>80 years		Interactionb P-value
	OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value
Death	0.52 (0.37–0.72)	<0.0001	0.38 (0.26–0.54)	<0.0001	0.68 (0.49–0.95)	0.02	0.44
MI	0.85 (0.62–1.16)	0.31	0.75 (0.52–1.09)	0.13	0.80 (0.50–1.30)	0.37	0.19
CVA	0.69 (0.38–1.25)	0.93	1.49 (0.86–2.57)	0.16	0.49 (0.22–1.09)	0.08	0.58
Triple endpoint (MACE)	0.69 (0.56–0.86)	<0.001	0.60 (0.47–0.76)	<0.0001	0.72 (0.54–0.95)	0.02	0.18
Rehospitalization	1.06 (0.93–1.20)	0.38	0.82 (0.69–0.98)	0.03	0.98 (0.75–1.27)	0.86	<0.01

CVA, cerebrovascular accident; MACE, major adverse cardiovascular events; MI, myocardial infarction.

^aAge, medical history (smoker, angina, myocardial infarction, heart failure, coronary intervention, PCI, CABG, diabetes, hypertension, hyperlipidaemia, renal insufficiency), Killip class, GRACE risk score, inhospital events (recurrent ischaemic symptoms, congestive heart failure/pulmonary oedema, cardiogenic shock, cardiac arrest/ventricular fibrillation, atrial fibrillation or flutter, sustained ventricular tachycardia, non-CABG-related major bleeding).

^bTesting the interaction between age as a continuous variable and invasive treatment.

Multiple logistic regression analysis, adjusted for baseline characteristics and inhospital events, confirmed the benefit of revascularization on the primary study endpoints (Table 5), with statistically significant reductions not only in the incidence of the combined triple endpoint but also in mortality alone at 6 months.

Discussion

Numerous randomized trials have demonstrated improved clinical outcomes in high-risk patients with NSTE-ACS when treated aggressively with early angiography and revascularization, where considered appropriate.^15–17 Elderly patients, particularly those with multiple co-morbidities, are poorly represented in these trials. In addition, in previous studies of unstable angina and NSTEMI, investigators have almost universally reported that the use of invasive cardiac procedures declines as patients get older.^5–7,18,19 This practice pattern is confirmed in the current analysis from the GRACE registry, with only 33% of very elderly and 55% of elderly patients undergoing angiography following presentation with a high-risk NSTE-ACS compared with 67% of young patients. This finding exists despite higher risk features, including a higher prevalence of heart failure and severe renal insufficiency in the elderly and very elderly groups, diabetes in the elderly, and a higher overall GRACE risk score noted with advancing patient years.

Clinicians' reluctance to use an invasive strategy of risk stratification and treatment for elderly patients with ACS is potentially justified by a perceived higher risk of complications. In an analysis from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry of management strategies in patients with suspected unstable angina and NSTEMI, Yusuf et al.⁶ observed a higher risk of stroke associated with an invasive management strategy. In contrast, Bach et al.⁸ did not report an increased rate of stroke in elderly patients undergoing coronary intervention in subset analysis of the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-Thrombolysis in Myocardial Infarction (TIMI) 18 trial. Our findings are consistent with this study, with no observed increase in the incidence of stroke either in hospital or at 6-month follow-up. Major bleeding was, however, more frequent among elderly and very elderly patients, with the highest incidence (7%) noted in very elderly patients undergoing a revascularization strategy. This complication was encountered despite lower use of glycoprotein IIb/IIIa receptor blockers and thienopyridines, and has been reported previously.⁸

Cost considerations, particularly for healthcare systems with limited resources, may influence patient selection for invasive treatment. An invasive strategy has, however, been reported recently by the Trial of Invasive vs. Medical therapy in Elderly patients (TIME) investigators to be cost-effective in an elderly cohort with chronic limiting angina at 12 months.²⁰ Cost should not therefore be used as an argument against invasive management in the elderly population.

Why coronary angiography was not undertaken in individual patients is difficult to ascertain, as GRACE is a registry of real-world practice. As such, registry patients tend to be sicker, with more co-morbidities than those enrolled in randomized clinical trials.²¹ These factors are likely to heavily influence patient selection for an invasive strategy. Nevertheless, when cardiac catheterization was undertaken for further risk stratification of high-risk patients with NSTE-ACS, revascularization was subsequently performed in over two-thirds of patients in all age cohorts. No increase in the incidence of stroke was noted at discharge or at 6-month follow-up in patients selected for revascularization. A strong mortality benefit appeared to be associated with revascularization, which was independent of age. This was noted both in hospital and at 6 months. The rate of myocardial infarction was also lower in the elderly and very elderly groups. Similar findings have been reported by the TIMI group.⁸ Although no mortality benefit was noted at 6 months in the TIME trial of elderly patients with limiting angina randomized to revascularization or medical therapy, a significant improvement in symptoms and quality of life was seen with revascularization, with a small early intervention-associated hazard.²² Follow-up at 4 years shows a durable beneficial effect of revascularization on angina status and quality of life, with a large proportion (43%) of medically treated patients requiring subsequent revascularization for refractory angina. Furthermore, in the TIME trial, a survival benefit was noted in revascularized patients within 1 year of randomization.²³ Our findings in a population of ACS patients with 6 months of follow-up are consistent with this.

Study strengths and limitations

GRACE is the largest multinational registry to include the complete spectrum of patients with ACS, including almost 70 000 patients from 14 countries. The participating clusters reflect regional practices and outcomes, but do not necessarily reflect practice for specific countries. Standardized criteria are employed for defining ACS, and hospital outcomes and rigorous quality control and audit measures are employed. Real-life studies such as GRACE offer the advantage that they provide data on a heterogeneous patient population that includes groups that are often under-represented in randomized trials, such the elderly. GRACE provides a representative sample of patients with ACS who are treated in a variety of hospital and healthcare systems. Nevertheless, as a non-randomized observational study, GRACE is subject to certain inherent limitations and potential biases including the collection of non-randomized data, missing or incomplete information, and potential confounding by drug indication or other unmeasured covariates. In this study, this relates in particular to our inability to report why angiography was not undertaken in high-risk patients, which must be kept in mind when interpreting the study results. Our findings should be regarded as hypothesis-generating, requiring confirmation in further studies. The American Heart Association, in collaboration with the Society of Geriatric Cardiology, has recently recommended increased enrolment of elderly subjects proportionate to their prevalence among the treated population. Outcomes of particular relevance to the elderly, such as quality of life, physical function, and independence, should be included in trial design.²⁴

Conclusion

The results of this large, contemporary, real-life study highlight a low rate of coronary angiography in elderly and very elderly patients with a high-risk NSTE-ACS. However, when coronary angiography is performed, revascularization is undertaken as frequently as in younger patients, with a low stroke rate. A significant mortality benefit—after adjustment for variables, which importantly included inhospital events—was associated with an invasive approach at 6 months. These results are consistent with the published literature and suggest that advanced age alone should not be regarded as a contraindication to invasive management following presentation with a high-risk ACS.

Funding

GRACE is supported by an unrestricted educational grant from sanofi-aventis to the Center for Outcomes Research, University of Massachusetts Medical School.

Acknowledgements

The authors thank the physicians and nurses participating in GRACE. Further information about the project can be found at www.outcomes.org/grace. The authors are grateful to Sophie Rushton-Smith, who provided editorial support and was funded by sanofi-aventis.

Conflict of interest: none declared.