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Comparison of Outcomes of Acute Coronary Syndrome in Patients ≥80 Years Versus Those <80 Years in Israel from 2000 to 2013
Comparison of Outcomes of Acute Coronary Syndrome in Patients ≥80 Years Versus Those <80 Years in Israel from 2000 to 2013 Michael Shechter, MD, MAa,b,*, Roy Rubinstein, MScb,†, Ilan Goldenberg, MDa,b, and Shlomi Matetzki, MDa,b on behalf of the Acute Coronary Syndrome Israel Survey (ACSIS) Although patients ≥80 years old constitute the fastest-growing segment of the population and have a high prevalence of coronary artery disease, few data exist regarding the outcome of octogenarians with acute coronary syndrome (ACS). In a retrospective study based on data of 13,432 ACS patients who were enrolled in the ACS Israel Survey, we first evaluated the clinical outcome of 1,731 ACS patients ≥80 years (13%) compared with 11,701 ACS patients <80 years (87%) hospitalized during 2000 to 2013. Second, we evaluated the clinical outcome of patients ≥80 years hospitalized during the 2000 to 2006 (“early”) period (n = 1,037) compared with those of the same age group of patients hospitalized during the 2008 to 2013 (“late”) period (n = 694). Implementation of the ACS AHA/ACC/ESC therapeutic guidelines was lower in ACS patients ≥80 years compared with patients <80 years. Multivariate Cox regression analysis demonstrated a worse 1-year survival rate in the ACS patients ≥80 years compared with those <80 years. During the late period, patients ≥80 years were more frequently treated with guideline-recommended therapies compared with patients from the same age group who were hospitalized in the early period. Multivariate Cox regression analysis demonstrated a better 1-year survival rate of patients ≥80 years during the late period compared with the early period (hazard ratio 1.17, 95% confidence interval 1.15 to 1.61; p = 0.01). In addition, adverse outcome rates of ACS patients ≥80 years were significantly higher compared with those of patients <80 years. However, survival rates of ACS patients ≥80 years were improved over the 200 to 2013 period. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:1230–1237) This study aimed to evaluate the treatment and clinical outcome in acute coronary syndrome (ACS) patients ≥80 years compared with those aged <80 years in Israel over the 2000 to 2013 period. The second objective was to evaluate trends in treatment and mortality rates of ACS patients aged ≥80 years over the same period. We consider this study to contribute to the understanding of age-related differences in the treatment and outcome of ACS patients as well as to recognize the effect of changes in the rate of use of guidelinerecommended therapy1,2 on the outcome of elderly ACS patients, thereby enhancing current evidence in this field. Methods The ACS Israel Survey (ACSIS) registry is a biannual prospective national survey of all patients with ACS hospitalized a
Leviev Heart Center, Chaim Sheba Medical Center, Tel Hashomer, Israel; and bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received May 12, 2017; revised manuscript received and accepted July 7, 2017. † This work was performed in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Part of this study was presented as an abstract at the European Society of Cardiology Annual Meetings in London, August 2015. See page 1236 for disclosure information. *Corresponding author: Tel: +972 3 5302617; fax: +972 3 6780581. E-mail address: [email protected] (M. Shechter). 0002-9149/© 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.07.003
in 25 coronary care units and cardiology wards in all general hospitals in Israel over a 2-month period (March to April).3,4 Demographic, historical, and clinical data were recorded on prespecified forms for all admitted patients diagnosed with ACS. Admission and discharge diagnoses were recorded by the attending physicians based on clinical, electrocardiographic, and biochemical criteria. Patient management was at the discretion of the attending physicians. All patients signed an informed consent for the ACSIS trial participation in each medical center, and each institution got a priori approval of its human research committee. The present study is a retrospective study based on data of 13,432 ACS patients who were enrolled in the ACSIS during the years 2000 to 2013. The study was performed in 2 stages. First, we evaluated the clinical outcomes of 1,731 ACS patients ≥80 years (13%) compared with those of 11,701 ACS patients <80 years (87%) hospitalized during the 2000 to 2013 period. Second, we evaluated clinical outcome of 1,731 ACS patients aged ≥80 years hospitalized during 2000 to 2006, the “early” period (n = 1,037) compared with those patients from the same age group hospitalized during 2008 to 2013, the “late” period (n = 694). Characteristics of study participants were compared using a chi-square test for categorical variables and Student’s t test or Wilcoxon rank tests for continuous variables. The Kruskal– Wallis test was used for comparison of non-normally distributed continuous variables. The probability of allcause mortality during 30-day and 1-year intervals was graphically displayed using the Kaplan–Meier method. Cox www.ajconline.org
Coronary Artery Disease/Outcomes of Acute Coronary Syndrome Octogenerians
proportional hazard multivariate-adjusted survival models were used to evaluate the independent effects of smoking and survey period on 30-day and 1-year all-cause mortality. To assess the specific contribution of the treatment period on allcause mortality, we created several Cox proportional hazard models with all-cause mortality as the dependent variable and potential confounders as independent variables. The following factors were prespecified as covariates in the multivariate survival models: hospitalization period, gender, age, history of premature familial cardiovascular disease, and previous cardiovascular co-morbidities and procedures: dyslipidemia, hypertension, diabetes mellitus, myocardial infarction (MI), angina pectoris, percutaneous coronary intervention (PCI), coronary artery bypass grafting, congestive heart failure (CHF), chronic renal failure, cerebrovascular accident/transient ischemic attack, and peripheral vascular disease. We also used logistic regression modeling. SPSS software (SPSS Inc., Chicago, IL) was used for all analyses. A p value of <0.05 was considered to indicate statistical significance for all tests. Results Baseline characteristics, given therapies since admission, and clinical outcomes of all study patients divided into 2 age groups are listed in Table 1. The study cohort comprised 13,432 ACS patients, of whom 1,731 (13%) were ≥80 years and 11,701 (87%) were <80 years. Interestingly, despite the progressive increment in life expectancy over the last decades, the hospitalization rate of patients ≥80 years among the overall hospitalized patients remained steady (~12%) during the 2000 to 2013 period. Female rates in both age groups (<80 years and ≥80 years) were lower than male rates but doubled in the older compared with the younger group (43% vs 21%; p < 0.001). Generally, ACS patients ≥80 years had lower rates of cardiovascular risk factors except hypertension. ACS patients ≥80 years had higher cardiovascular co-morbidities including chronic renal failure, MIs, CHF, and previous coronary artery bypass grafting but lower incidence of previous PCIs compared with those <80 years. Concomitant cardiovascular medications, except statins and hypoglycemic agents, were more common in those ≥80 years compared with those <80 years. Although more ACS patients ≥80 years arrived at the hospital in mobile intensive care cardiac units or regular ambulance services compared with those aged <80 years, time from symptom onset to emergency room (ER) admission and doorto-balloon time were longer in the older patient group. In addition, ACS patients ≥80 years presented more often to the ER with a higher degree of heart failure (Killip class >2), had a higher incidence of left ventricular ejection fraction <50% per echocardiography, and a higher incidence of large MIs measured by total cardiac enzymes (CPK elevation) compared with patients <80 years. Upon hospitalization, ACS patients aged ≥80 years were significantly less likely to receive reperfusion therapy compared with patients aged <80 years, including primary PCI in ST elevation myocardial infarction (44.8% vs 63.8%, p < 0.0001, respectively). Throughout hospitalization, ACS patients ≥80 years compared with those <80 years were significantly less likely to receive guideline-recommended pharmacotherapies, such as
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dual antiplatelet therapy, unfractionated heparin anticoagulation therapy, β blockers, and statins. In contrast, some medications were more frequently given to patients ≥80 years compared with those <80 years, including diuretics and calcium channel blockers. ACS patients ≥80 years compared with patients <80 years were less likely to receive secondary-prevention medical therapies such as angiotensin converting enzyme inhibitors and had a significantly lower referral rate for cardiac rehabilitation programs, although a cardiac rehabilitation program has been demonstrated to reduce post-ACS all-age mortality rate by 20%.5,6 Over 80 versus under 80 ACS patients had higher inhospital major adverse cardiac events (including re-MI, postMI angina, ischemic stroke, high-degree atrioventricular block, acute renal failure and, major bleeding) and also had fourfold to fivefold higher mortality rates. Figure 1 demonstrates the Kaplan–Meier survival curve, adjusted to the risk factors and co-morbidities that are mentioned in Table 1, demonstrated a lower survival rate probability across the first year after hospitalization in ACS patients ≥80 years compared with patients <80 years. Baseline characteristics, prehospital, in-hospital, and 30day therapy and clinical outcome of ACS patients ≥80 years by the 2 study periods are shown in Table 2. ACS patients hospitalized in the late period were older by about half a year, had higher prevalence of most of the evaluated cardiovascular risk factors, and had higher rates of previous MIs and chronic renal failure; however, no difference was found between the 2 periods in the prevalence of previous peripheral vascular disease, cerebrovascular accident, or CHF. In addition, patients in the late period received higher rates of concomitant medical cardiovascular treatment at home, before their current admission, and had higher prevalence of invasive cardiac procedure history, including a 20% higher incidence of previous PCIs compared with patients in the early period. Rates of arrival to intensive care cardiac unit increased over the study years, although time from symptom onset to ER arrival did not significantly change. Door-to-balloon and ER-to-first-ward times were also not changed across the 2 study periods. Despite the more complex
Figure 1. A Kaplan–Meier 1-year survival curve of acute coronary syndrome patients ≥80 years old (n = 1,730) versus patients <80 years (n = 11,692), adjusted for cardiovascular risk factors, co-morbidities, and hospitalization period (p = 0.01 by log-rank test).
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Table 1 Baseline characteristics, postadmission therapy and clinical outcomes by age group Variable
Age, years (mean ± SD) Men Women Dyslipidemia Hypertension Current smokers Diabetes mellitus Family history of CAD BMI (kg/m2), (mean ± SD) Prior MI Prior CABG Prior PCI Chronic renal failure PVD s/p CVA/TIA History of CHF Prior medications Aspirin Clopidogrel ACE-I/ARB Beta blockers Statins CCB Nitrates Aldosterone receptor antagonist Hypoglycemic agents Diuretics Means of arrival to hospital and time to treatment Mobile ICCU Regular ambulance Private car Time from symptoms onset to ER (median,IQR) (min) Time from ER to 1st ward (median,IQR) (min) Door to balloon time (median,IQR) (min) Killip class on admission 1 2 3 4 LVEF<50% rates LVEF <50% Post admission therapy Reperfusion therapy STEMI n. Reperfusion therapy in STEMI Thrombolysis Angio without PCI/urgent CABG Primary PCI Any PCI in STEMI Any PCI in all patients Use of IIb/IIIa antagonists In-hospital therapy Aspirin Clopidogrel Warfarin/oral anticoagulation UF heparin LMW heparin ACE-I/ARB Beta blockers
Age (years)
P value
<80 (n=11,692)
≥ 80 (n = 1,730)
60.6 ± 10.9 89.0% 21.0% 64.8% 54.9% 41.0% 35.0% 26.8% 28.2 ± 11.8 28.4% 9.5% 27.1% 8.5% 8.0% 7.1% 6.4%
84.6 ± 4.1 57.0% 43.0% 54.6% 78.4% 7.0% 33.4% 5.6% 26.4 ± 10.4 37.9% 13.7% 24.3% 26.6% 13.2% 14.7% 18.5%
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.2164 <0.0001 <0.0001 <0.0001 <0.0001 0.0136 <0.0001 <0.0001 <0.0001 <0.0001
46.1% 8.2% 35.0% 34.6% 42.8% 18.0% 10.4% 2.0% 22.4% 14.7%
58.7% 10.4% 50.1% 46.3% 44.6% 34.1% 24.5% 4.2% 21.1% 34.1%
<0.0001 0.0038 <0.0001 <0.0001 0.1835 <0.0001 <0.0001 0.0003 0.2614 <0.0001
35.0% 12.3% 47.3% 168 (85–481) 94 (41–180) 64 (38–105)
42.5% 18.3% 32.3% 189 (93–472) 117 (58–215) 78.5 (43–133)
0.001 0.001 0.001 0.02 <0.0001 <0.001
85.8% 8.4% 4.2% 1.4%
64.1% 19.7% 12.8% 3.3%
<0.001 <0.001 <0.001 <0.001
56%
70%
<0.001
5611 32.7% 11.0% 0.6% 25.1% 56.0% 63.7% 73.5%
671 18.8% 5.8% 0.3% 15.1% 44.8% 45.0% 72.4%
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.800
96.5% 68.4% 5.8% 62.3% 48.9% 71.2% 80.5%
93.0% 59.0% 7.6% 55.1% 50.9% 70.7% 71.6%
<0.0001 <0.0001 0.0024 <0.0001 0.1227 0.6605 <0.0001 (continued on next page)
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Table 1 (continued) Variable
Age (years)
P value
<80 (n=11,692)
≥ 80 (n = 1,730)
23.9% 79.9% 18% 37.0% 15.5%
53.8% 68.6% 32% 46.1% 12.1%
<0.0001 <0.0001 <0.0001 <0.0001 0.0028
94.8% 63.6% 83.5% 71.6% 15.6% 80.1% 48.0% 20.5%
86.2% 51.3% 69.4% 66.7% 22.2% 68.5% 26.4% 11.0%
<0.0001 <0.0001 <0.0001 0.0003 <0.0001 <0.0001 <0.0001 <0.001
6.0% 3.0% 169 (1.5%) 634 (5.4%) 52 (0.8%) 65 (0.6%) 0.2% 2.3% 0.7% 4.8% 1.0%
17.1% 8.2% 36 (2.1%) 122 (7.1%) 10 (1.1%) 23 (1.3%) 1.7% 4.2% 1.6% 16.1% 2.6%
<0.0001 <0.0001 0.0426 0.005 0.4125 0.0019 <0.0001 <0.0001 0.0010 <0.0001 <0.0001
235 (2.0%) 244 (2.1%) 429 (3.7%) 827 (7.2%)
177 (10.2%) 164 (9.5%) 268 (15.6%) 502 (29.4%)
<0.0001 <0.0001 <0.0001 <0.0001
Diuretics Statins CCB Nitrates Hypoglycemic agents Therapy at 30-day follow-up Aspirin Clopidogrel Statins ACE-I/ARB CCB Beta blockers Referral to rehabilitation program Participating in a rehabilitation program Clinical outcomes In-hospital complications Killip 3 Killip 4 Re MI Post MI angina Stent thrombosis Ischemic stroke Free wall rupture High degree AV block TIA/CVA Acute renal failure Major bleeding Death rates In-hospital death 7-day mortality 30-day mortality 1-year mortality
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers; AV = atrioventricular; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCB = calcium channel blockers; CHF = congestive heart failure; CVA = cerebrovascular accident; ER = emergency room; ICCU = Intensive Cardiac-Care Unit; IQR = interquartile range; LMW = low molecular weight; LVEF = left ventricle ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease; SD = standard deviation; STEMI = ST elevation myocardial infarction; TIA = transient ischemic attack; UF = unfractionated. Dyslipidemia was defined as total cholesterol > 200 mg/dl or patients on lipid lowering therapy.
health status of elderly ACS patients admitted in the late period, they had lower rates of overt CHF symptoms on admission, reflected in the lower Killip class, as well as lower incidence of left ventricular ejection fraction <50%, compared with those in the early period. Throughout the study period, PCIs became more common during hospitalization, and rates of primary PCI more than doubled (10.2% in the early period vs 25% in the late period; p < 0.0001). However, thrombolytic therapy declined according to the trends in guideline recommendations.1,2 Accordingly, there was a marked increment in the usage of guidelinerecommended medications, including dual antiplatelet therapy (42.3% of clopidogrel prescription in the early period vs 83.6% in the late period; p < 0.0001), statins (53.1% vs 91.2%; p < 0.0001), angiotensin converting enzyme inhibitors, β blockers, and hypoglycemic agents across the study years; however, there was a decline in the use of nitrates and digoxin. Increased rates of most guideline-recommended therapy use were
found at 30-day follow-up too, as well as an increment in referral and participation in cardiac rehabilitation programs. Most in-hospital complication rates did not change across the study years, except 3, which improved over the study period (worsening of Killip class to third degree, post-MI angina, and acute renal failure). There was a significant decline in in-hospital, 7-day, and 1-year mortality rates in ACS patients ≥80 years hospitalized in the late compared with the early period. Figure 2 shows a 1-year survival curve, adjusted to the risk factors and previous co-morbidities as in Table 2, which indicates a higher survival probability across 1-year follow-up in the late compared with the early period (HR 1.17, 95% confidence interval 1.15 to 1.61; p = 0.01]. Discussion The current study demonstrated that ACS patients ≥80 years were treated less with guideline-recommended therapies and had
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Table 2 Baseline characteristics, given therapies since admission and clinical outcomes of patients ≥80 years by study period Variable Baseline characteristics Age, (years) (mean ± SD) Men Women Dyslipidemia Hypertension Current smokers Diabetes mellitus Family history of CAD BMI (kg/m2), (mean ± SD) Prior to admission cardiovascular morbidity s/p MI s/p CABG s/p PCI Chronic renal failure PVD s/p CVA/TIA History of CHF Prior concomitant medications (at home) Aspirin Clopidogrel ACE-I/ARB Beta blockers Statins CCB Nitrates Aldosterone receptor antagonist Hypoglycemic agents Diuretics Means of arrival at hospital and time to treatment Mobile ICCU Regular ambulance Private car Time from symptom onset to ER (min) (median, IQR) Time from ER to 1st ward (min) (median, IQR) Door to balloon time (min) (median, IQR) Killip class on admission ≥2 ≥3 LVEF <50% Post admission therapy Reperfusion therapy STEMI, n Reperfusion therapy STEMI Thrombolysis Angio without PCI/urgent CABG Primary PCI Use of IIb/IIIa antagonists Any PCI in STEMI Use of IIb/IIIa antagonists Any PCI in all patients Use of IIb/IIIa antagonists In-hospital therapy Aspirin Clopidogrel Warfarin/oral anticoagulation UF heparin LMW heparin ACE-I/ARB Beta blockers Diuretics
2000–2006 (n = 1,037)
2008–2013 (n = 694)
P value
84.4 ± 4.1 57% 43% 40.9% 73.9% 7.1% 30.0% 4.0% 26.0 ± 4.0
85.0 ± 4.1 57% 43% 75.0% 85.1% 7.1% 38.5% 8.4% 27.4 ± 17.7
0.0002 0.9925 0.9925 <0.0001 <0.0001 0.98 0.0025 0.0002 0.4119
35.7% 12.0% 15.7% 24.2% 14.2% 15.5% 18.6%
41.3% 16.5% 37.0% 30.2% 11.7% 13.6% 18.5%
0.0181 0.0084 <0.0001 0.0057 0.1304 0.2601 0.9759
57.6% 4.7% 46.8% 43.5% 33.1% 31.5% 30.4% 2.0% 18.9% 34.0%
60.0% 17.0% 53.7% 49.7% 58.2% 37.2% 17.5% 4.2% 23.7% 34.2%
0.3356 <0.0001 0.0075 0.0162 <0.0001 0.0215 <0.0001 0.0003 0.0219 0.9537
40.5% 21.0% 31.7% 189 (95–480) 110 (59–198) 71 (43–134)
45.1% 14.5% 33.0% 188 (90–453) 128 (57–229) 88 (45–133)
0.009 0.009 0.009 0.400 0.120 0.270
40.4% 18.6% 73%
28.9% 12.5% 63%
<0.001 <0.001 <0.001
438 18.6% 8.3% 0.1% 10.2% 52.6% 43.0% 52.6% 37.8% 52.6%
233 19.1% 0.8% 0.8% 25.0% 82.0% 46.8% 82.0% 53.9% 82.0%
0.800 <0.0001 <0.0001 <0.0001 <0.01 0.05 0.01 <0.0001 0.01
92.6% 42.3% 7.7% 53.1% 51.4% 68.5% 66.7% 55.4%
93.7% 83.6% 7.5% 58.1% 50.0% 74.1% 78.8% 51.3%
0.4120 <0.0001 0.8741 0.0430 0.5684 0.0128 <0.0001 0.0972 (continued on next page)
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Table 2 (continued) Variable
2000–2006 (n = 1,037)
2008–2013 (n = 694)
P value
53.1% 6.7% 57.8% 9.7%
91.2% 3.5% 33.1% 15.7%
<0.0001 0.0032 <0.0001 0.0018
85.0% 38.1% 56.5% 66.4% 16.5% 64.8% 13.6% 9.2%
88.0% 70.0% 88.0% 67.3% 28.4% 73.9% 31.0% 50.0%
0.0903 <0.0001 <0.0001 0.6916 <0.0001 0.0009 <0.0001 <0.001
19.9% 8.9% 25 (2.4%) 96 (9.4%) 0 (0%) 14 (1.4%) 1.9% 4.6% 1.5% 18.1% 2.4%
13.0% 7.2% 11 (1.6%) 26 (3.8%) 10 (1.4%) 9 (1.3%) 1.3% 3.7% 1.7% 13.1% 2.9%
0.0001 0.2191 0.2276 0.0001 0.0519 0.9099 0.3101 0.4019 0.7634 0.0058 0.5504
120 (11.6%) 112 (10.8%) 177 (17.1%) 327 (31.7%)
57 (8.2%) 50 (7.8%) 85 (13.7%) 118 (26.6%)
0.0238 0.0463 0.0705 0.01
Statins Digoxin Nitrates Hypoglycemic agents Therapy at 30-day follow-up Aspirin Clopidogrel Statins ACE-I/ARB CCB Beta blockers Referral to rehabilitation program Participating in a rehabilitation program Clinical outcomes In-hospital complications Killip 3 Killip 4 Re MI Post MI angina Stent thrombosis Ischemic stroke Free wall rupture High degree AV block TIA/CVA Acute renal failure Major bleeding Mortality rates In-hospital death 7-day mortality 30-day mortality 1-year mortality
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers; AV = atrioventricular; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCB = calcium channel blockers; CHF = congestive heart failure; CVA = cerebrovascular accident; ER = emergency room; ICCU = Intensive Cardiac-Care Unit; IQR = interquartile range; LMW = low molecular weight; LVEF = left ventricle ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease; SD = standard deviation; STEMI = ST elevation myocardial infarction; TIA = transient ischemic attack; UF = unfractionated. Dyslipidemia was defined as total cholesterol > 200 mg/dl or patients on lipid lowering therapy.
worse in-hospital and postdischarge prognosis compared with patients <80 years. Nevertheless, analysis showed raised guidelinerecommended therapy rates (invasive, medical, and rehabilitation) in those ACS patients ≥80 years during 2000 to 2013, with matching progressive improved clinical outcomes. Cardiovascular co-morbidity rates were higher in elderly patients, consistent with previous reports,7,8 which correspond with the high rates of previous concomitant cardiovascular pharmacotherapy found in the elderly group. Another significant difference between the 2 age groups is the longer “door-to-balloon time” in the older age group. This finding is commensurate with previous studies9,10 and might be explained by a longer period of indecision regarding the correct treatment as well as longer procedural delays in the elderly patients. The prehospital delays may be partially explained by atypical symptoms,10 which might make the patients delay recognition of the need to call for help. These delays should alert the medical teams, especially regarding ACS patients ≥80 years who tend to suffer more comorbidities, larger MIs, and a relatively higher mortality risk than their younger counterparts.
Figure 2. A Kaplan–Meier 1-year survival curve of all patients ≥80 years stratified to 2 study periods: patients hospitalized in the early 2000 to 2006 period (lineal line) and late, 2008 to 2013 period (continuous line). p = 0.01 by log-rank test (hazard ratio 1.17, 95% CI 1.15 to 1.61; p = 0.01), adjusted for cardiovascular risk factors, co-morbidities, and hospitalization period.
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Unfortunately, although ACS patients ≥80 years who were hospitalized had larger MIs, lower left ventricular ejection fractions, and higher rates of clinical CHF, they received lower rates of invasive, medical, and rehabilitation guideline– recommended therapies. These findings concur with previous reports.11–16 Late arrival, atypical symptoms, and doctor’s concerns for potential treatment-induced adverse effects and coexisting co-morbid geriatric conditions may contribute to the decreased usage of guideline-recommended therapy even among elderly patients who are eligible for those therapies.10 Increased guideline-recommended therapy use and the corresponding decreasing mortality rate in elderly ACS patients were also demonstrated in previous studies.17–21 Nevertheless, improvement trends in elderly patient outcomes are not absolute. For example, a study that evaluated trends in mortality rates in Croatian ACS patients during 1990 to 2010 demonstrated reduced mortality rate in all age groups except in women >75 years and men >85 years.22 Moreover, in those populations an increment in mortality rates over the period was demonstrated. Those findings may be partially explained by the low access of those populations to guidelinerecommended therapies. Schoenenberger et al23 has recently published a comparison over 3 periods during the years 2000 to 2012 between treatments and outcomes of ACS patients ≥70 years in Switzerland. Both Schoenenberger et al’s and our studies found an increment in previous admission risk factors and co-morbidity rates in elderly patients across the years. Notwithstanding, both studies found reduced mortality and adverse outcome rates across the years that may indicate the significant benefit of using guideline-recommended therapies, even among elderly patients with complex illnesses. We hypothesize that the main explanation for the increment in rates of previous risk factors and co-morbidities is the increased use of guideline-recommended therapies, which enables prolongation of life despite a complex health status. In the past, many patients who suffered from those risk factors and co-morbidities died before they reached their ninth decade. A noteworthy difference between the 2 studies is the higher mortality rate of patients ≥80 years in Schoenenberger et al’s study compared with our current study during the early period (16.3% in octogenarians and 26.5% in nonagenarians in Schoenenberger et al’s study during 2001 to 2004 vs 11.6% in the overall population of patients ≥80 years in our study during 2000 to 2006) or the late period (12.6% in octogenarians and 23% in nonagenarians in Schoenenberger et al’s study during 2009 to 2012 vs 8.2% in the overall population of patients ≥80 years in our study during 2008 to 2013). This difference may be attributed to a shorter duration time between symptom onset to ER admission in our study (189 [90 to 480] minutes without change between the periods) compared with Schoenenberger et al’s study (283 [130 to 765] minutes in the early period and 240 [120 to 637] minutes in the late period). Reduced duration time from symptom onset until ER admission in Schoenenberger et al’s study may provide another possible explanation for the reduction in mortality rates over the years. In our current study, however, no change was demonstrated regarding prehospital delay, thereby strengthening our hypothesis that improved outcome in elderly
patients is mainly derived from the enhanced use of guidelinerecommended therapies. The present study has some limitations. First, our study was based on registry data and therefore may exhibit some limitations (as selection bias). Second, this is a retrospective study, and thus, causal relation between therapy usage rates and outcome trends cannot be associated. Third, the ACSIS survey is a biannual study carried out during the months March to April. This 2-month period might not represent the whole year adequately, and this could influence morbidity and mortality of ACS. In conclusion, ACS patients ≥80 years have a worse prognosis compared with patients <80 years; nevertheless, their clinical outcome improved significantly over the 2000 to 2013 period, which may be well explained by the increment in guideline-recommended therapy usage rates in the elderly patients. Improved alertness and awareness to the need of a high index of suspicion and prompt treatment in elderly patients with ACS, as well as assimilation of the benefits of early invasive reperfusion therapy and pharmacologic and rehabilitation guideline-recommended therapy, may improve the prognosis of this high-risk population. Disclosures The authors state that no conflict of interest exists regarding the possible publication of this article. The corresponding author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso JE, Tracy CM, Woo YJ, Zhao DX, CF/AHA Task Force. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:529–555. 2. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL, 2012 Writing Committee Members, American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2012;126:875–910. 3. Kornowski R. The ACSIS Registry and primary angioplasty following coronary bypass surgery. Catheter Cardiovasc Interv 2011;78:537– 539. 4. Segev A, Matetzky S, Danenberg H, Fefer P, Bubyr L, Zahger D, Roguin A, Gottlieb S, Kornowski R. Contemporary use and outcome of percutaneous coronary interventions in patients with acute coronary syndromes: insights from the 2010 ACSIS and ACSIS-PCI surveys. EuroIntervention 2012;8:465–469. 5. O’Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM, Paffenbarger RS Jr, Hennekens CH. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989;80:234–244. 6. Menezes AR, Lavie CJ, Milani RV, Arena RA, Church TS. Cardiac rehabilitation and exercise therapy in the elderly: should we invest in the aged? J Geriatr Cardiol 2012;9:68–75. 7. Devlin G, Gore JM, Elliott J, Wijesinghe N, Eagle KA, Avezum Á, Huang W, Brieger D. Management and 6-month outcomes in elderly and very
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elderly patients with high-risk non-ST-elevation acute coronary syndromes: the Global Registry of Acute Coronary Events. Eur Heart J 2008;29:1275–1282. Forman DE, Chen AY, Wiviott SD, Wang TY, Magid DJ, Alexander KP. Comparison of outcomes in patients aged <75, 75 to 84, and ≥85 years with ST-elevation myocardial infarction (from the ACTION Registry-GWTG). Am J Cardiol 2010;106:1382–1388. Fach A, Bünger S, Zabrocki R, Schmucker J, Conradi P, Garstka D, Fiehn E, Hambrecht R, Wienbergen H. Comparison of outcomes of patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention analyzed by age groups (<75, 75 to 85, and >85 years); (results from the Bremen STEMI Registry). Am J Cardiol 2015;116:1802–1809. Alexander KP, Newby LK, Armstrong PW, Cannon CP, Gibler WB, Rich MW, Van de Werf F, White HD, Weaver WD, Naylor MD, Gore JM, Krumholz HM, Ohman EM, American Heart Association Council on Clinical Cardiology, Society of Geriatric Cardiology. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: 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;115:2570–2589. Avezum A, Makdisse M, Spencer F, Gore JM, Fox KA, Montalescot G, Eagle KA, White K, Mehta RH, Knobel E, Collet JP, GRACE Investigators. Impact of age on management and outcome of acute coronary syndrome: observations from the Global Registry of Acute Coronary Events (GRACE). Am Heart J 2005;149:67–73. Schoenenberger AW, Radovanovic D, Stauffer JC, Windecker S, Urban P, Eberli FR, Stuck AE, Gutzwiller F, Erne P, Acute Myocardial Infarction in Switzerland Plus Investigators. Age-related differences in the use of guideline-recommended medical and interventional therapies for acute coronary syndromes: a cohort study. J Am Geriatr Soc 2008;56:510– 516. Skolnick AH, Alexander KP, Chen AY, Roe MT, Pollack CV Jr, Ohman EM, Rumsfeld JS, Gibler WB, Peterson ED, Cohen DJ. Characteristics, management, and outcomes of 5,557 patients age > or =90 years with acute coronary syndromes: results from the CRUSADE Initiative. J Am Coll Cardiol 2007;49:1790–1797. Rosengren A, Wallentin L, Simoons M, Gitt AK, Behar S, Battler A, Hasdai D. Age, clinical presentation, and outcome of acute coronary
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syndromes in the Euroheart Acute Coronary Syndrome Survey. Eur Heart J 2006;27:789–795. Smith LG, Herlitz J, Karlsson T, Berger AK, Luepker RV. 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. Zaman MJ, Stirling S, Shepstone L, Ryding A, Flather M, Bachmann M, Myint PK. The association between older age and receipt of care and outcomes in patients with acute coronary syndromes: a cohort study of the Myocardial Ischaemia National Audit Project (MINAP). Eur Heart J 2014;35:1551–1558. Gale CP, Allan V, Cattle BA, Hall AS, West RM, Timmis A, Gray HH, Deanfield J, Fox KA, Feltbower R. Trends in hospital treatments, including revascularisation, following acute myocardial infarction, 2003– 2010: a multilevel and relative survival analysis for the National Institute for Cardiovascular Outcomes Research (NICOR). Heart 2014;100:582– 589. Schiele F, Meneveau N, Seronde MF, Descotes-Genon V, Oettinger J, Ecarnot F, Bassand JP. Changes in management of elderly patients with myocardial infarction. Eur Heart J 2009;30:987–994. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010;362:2155–2165. Chin CT, Wang TY, Chen AY, Mathews R, Alexander KP, Roe MT, Peterson ED. Trends in outcomes among older patients with non–STsegment elevation myocardial infarction. Am Heart J 2014;167:36– 42. Gale CP, Cattle BA, Woolston A, Baxter PD, West TH, Simms AD, Blaxill J, Greenwood DC, Fox KA, West RM. Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003– 2010. Eur Heart J 2012;33:630–639. Vujcic IS, Sipetic SB, Dubljanin ES, Vlajinac HD. Trends in mortality rates from coronary heart disease in Belgrade (Serbia) during the period 1990–2010: a joinpoint regression analysis. BMC Cardiovasc Disord 2013;13:112. Schoenenberger AW, Radovanovic D, Windecker S, Iglesias JF, Pedrazzini G, Stuck AE, Erne P, AMIS Plus Investigators. Temporal trends in the treatment and outcomes of elderly patients with acute coronary syndrome. Eur Heart J 2016;37:1304–1311.
Leviev Heart Center, Chaim Sheba Medical Center, Tel Hashomer, Israel; and bSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received May 12, 2017; revised manuscript received and accepted July 7, 2017. † This work was performed in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Part of this study was presented as an abstract at the European Society of Cardiology Annual Meetings in London, August 2015. See page 1236 for disclosure information. *Corresponding author: Tel: +972 3 5302617; fax: +972 3 6780581. E-mail address: [email protected] (M. Shechter). 0002-9149/© 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.07.003
in 25 coronary care units and cardiology wards in all general hospitals in Israel over a 2-month period (March to April).3,4 Demographic, historical, and clinical data were recorded on prespecified forms for all admitted patients diagnosed with ACS. Admission and discharge diagnoses were recorded by the attending physicians based on clinical, electrocardiographic, and biochemical criteria. Patient management was at the discretion of the attending physicians. All patients signed an informed consent for the ACSIS trial participation in each medical center, and each institution got a priori approval of its human research committee. The present study is a retrospective study based on data of 13,432 ACS patients who were enrolled in the ACSIS during the years 2000 to 2013. The study was performed in 2 stages. First, we evaluated the clinical outcomes of 1,731 ACS patients ≥80 years (13%) compared with those of 11,701 ACS patients <80 years (87%) hospitalized during the 2000 to 2013 period. Second, we evaluated clinical outcome of 1,731 ACS patients aged ≥80 years hospitalized during 2000 to 2006, the “early” period (n = 1,037) compared with those patients from the same age group hospitalized during 2008 to 2013, the “late” period (n = 694). Characteristics of study participants were compared using a chi-square test for categorical variables and Student’s t test or Wilcoxon rank tests for continuous variables. The Kruskal– Wallis test was used for comparison of non-normally distributed continuous variables. The probability of allcause mortality during 30-day and 1-year intervals was graphically displayed using the Kaplan–Meier method. Cox www.ajconline.org
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proportional hazard multivariate-adjusted survival models were used to evaluate the independent effects of smoking and survey period on 30-day and 1-year all-cause mortality. To assess the specific contribution of the treatment period on allcause mortality, we created several Cox proportional hazard models with all-cause mortality as the dependent variable and potential confounders as independent variables. The following factors were prespecified as covariates in the multivariate survival models: hospitalization period, gender, age, history of premature familial cardiovascular disease, and previous cardiovascular co-morbidities and procedures: dyslipidemia, hypertension, diabetes mellitus, myocardial infarction (MI), angina pectoris, percutaneous coronary intervention (PCI), coronary artery bypass grafting, congestive heart failure (CHF), chronic renal failure, cerebrovascular accident/transient ischemic attack, and peripheral vascular disease. We also used logistic regression modeling. SPSS software (SPSS Inc., Chicago, IL) was used for all analyses. A p value of <0.05 was considered to indicate statistical significance for all tests. Results Baseline characteristics, given therapies since admission, and clinical outcomes of all study patients divided into 2 age groups are listed in Table 1. The study cohort comprised 13,432 ACS patients, of whom 1,731 (13%) were ≥80 years and 11,701 (87%) were <80 years. Interestingly, despite the progressive increment in life expectancy over the last decades, the hospitalization rate of patients ≥80 years among the overall hospitalized patients remained steady (~12%) during the 2000 to 2013 period. Female rates in both age groups (<80 years and ≥80 years) were lower than male rates but doubled in the older compared with the younger group (43% vs 21%; p < 0.001). Generally, ACS patients ≥80 years had lower rates of cardiovascular risk factors except hypertension. ACS patients ≥80 years had higher cardiovascular co-morbidities including chronic renal failure, MIs, CHF, and previous coronary artery bypass grafting but lower incidence of previous PCIs compared with those <80 years. Concomitant cardiovascular medications, except statins and hypoglycemic agents, were more common in those ≥80 years compared with those <80 years. Although more ACS patients ≥80 years arrived at the hospital in mobile intensive care cardiac units or regular ambulance services compared with those aged <80 years, time from symptom onset to emergency room (ER) admission and doorto-balloon time were longer in the older patient group. In addition, ACS patients ≥80 years presented more often to the ER with a higher degree of heart failure (Killip class >2), had a higher incidence of left ventricular ejection fraction <50% per echocardiography, and a higher incidence of large MIs measured by total cardiac enzymes (CPK elevation) compared with patients <80 years. Upon hospitalization, ACS patients aged ≥80 years were significantly less likely to receive reperfusion therapy compared with patients aged <80 years, including primary PCI in ST elevation myocardial infarction (44.8% vs 63.8%, p < 0.0001, respectively). Throughout hospitalization, ACS patients ≥80 years compared with those <80 years were significantly less likely to receive guideline-recommended pharmacotherapies, such as
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dual antiplatelet therapy, unfractionated heparin anticoagulation therapy, β blockers, and statins. In contrast, some medications were more frequently given to patients ≥80 years compared with those <80 years, including diuretics and calcium channel blockers. ACS patients ≥80 years compared with patients <80 years were less likely to receive secondary-prevention medical therapies such as angiotensin converting enzyme inhibitors and had a significantly lower referral rate for cardiac rehabilitation programs, although a cardiac rehabilitation program has been demonstrated to reduce post-ACS all-age mortality rate by 20%.5,6 Over 80 versus under 80 ACS patients had higher inhospital major adverse cardiac events (including re-MI, postMI angina, ischemic stroke, high-degree atrioventricular block, acute renal failure and, major bleeding) and also had fourfold to fivefold higher mortality rates. Figure 1 demonstrates the Kaplan–Meier survival curve, adjusted to the risk factors and co-morbidities that are mentioned in Table 1, demonstrated a lower survival rate probability across the first year after hospitalization in ACS patients ≥80 years compared with patients <80 years. Baseline characteristics, prehospital, in-hospital, and 30day therapy and clinical outcome of ACS patients ≥80 years by the 2 study periods are shown in Table 2. ACS patients hospitalized in the late period were older by about half a year, had higher prevalence of most of the evaluated cardiovascular risk factors, and had higher rates of previous MIs and chronic renal failure; however, no difference was found between the 2 periods in the prevalence of previous peripheral vascular disease, cerebrovascular accident, or CHF. In addition, patients in the late period received higher rates of concomitant medical cardiovascular treatment at home, before their current admission, and had higher prevalence of invasive cardiac procedure history, including a 20% higher incidence of previous PCIs compared with patients in the early period. Rates of arrival to intensive care cardiac unit increased over the study years, although time from symptom onset to ER arrival did not significantly change. Door-to-balloon and ER-to-first-ward times were also not changed across the 2 study periods. Despite the more complex
Figure 1. A Kaplan–Meier 1-year survival curve of acute coronary syndrome patients ≥80 years old (n = 1,730) versus patients <80 years (n = 11,692), adjusted for cardiovascular risk factors, co-morbidities, and hospitalization period (p = 0.01 by log-rank test).
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Table 1 Baseline characteristics, postadmission therapy and clinical outcomes by age group Variable
Age, years (mean ± SD) Men Women Dyslipidemia Hypertension Current smokers Diabetes mellitus Family history of CAD BMI (kg/m2), (mean ± SD) Prior MI Prior CABG Prior PCI Chronic renal failure PVD s/p CVA/TIA History of CHF Prior medications Aspirin Clopidogrel ACE-I/ARB Beta blockers Statins CCB Nitrates Aldosterone receptor antagonist Hypoglycemic agents Diuretics Means of arrival to hospital and time to treatment Mobile ICCU Regular ambulance Private car Time from symptoms onset to ER (median,IQR) (min) Time from ER to 1st ward (median,IQR) (min) Door to balloon time (median,IQR) (min) Killip class on admission 1 2 3 4 LVEF<50% rates LVEF <50% Post admission therapy Reperfusion therapy STEMI n. Reperfusion therapy in STEMI Thrombolysis Angio without PCI/urgent CABG Primary PCI Any PCI in STEMI Any PCI in all patients Use of IIb/IIIa antagonists In-hospital therapy Aspirin Clopidogrel Warfarin/oral anticoagulation UF heparin LMW heparin ACE-I/ARB Beta blockers
Age (years)
P value
<80 (n=11,692)
≥ 80 (n = 1,730)
60.6 ± 10.9 89.0% 21.0% 64.8% 54.9% 41.0% 35.0% 26.8% 28.2 ± 11.8 28.4% 9.5% 27.1% 8.5% 8.0% 7.1% 6.4%
84.6 ± 4.1 57.0% 43.0% 54.6% 78.4% 7.0% 33.4% 5.6% 26.4 ± 10.4 37.9% 13.7% 24.3% 26.6% 13.2% 14.7% 18.5%
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.2164 <0.0001 <0.0001 <0.0001 <0.0001 0.0136 <0.0001 <0.0001 <0.0001 <0.0001
46.1% 8.2% 35.0% 34.6% 42.8% 18.0% 10.4% 2.0% 22.4% 14.7%
58.7% 10.4% 50.1% 46.3% 44.6% 34.1% 24.5% 4.2% 21.1% 34.1%
<0.0001 0.0038 <0.0001 <0.0001 0.1835 <0.0001 <0.0001 0.0003 0.2614 <0.0001
35.0% 12.3% 47.3% 168 (85–481) 94 (41–180) 64 (38–105)
42.5% 18.3% 32.3% 189 (93–472) 117 (58–215) 78.5 (43–133)
0.001 0.001 0.001 0.02 <0.0001 <0.001
85.8% 8.4% 4.2% 1.4%
64.1% 19.7% 12.8% 3.3%
<0.001 <0.001 <0.001 <0.001
56%
70%
<0.001
5611 32.7% 11.0% 0.6% 25.1% 56.0% 63.7% 73.5%
671 18.8% 5.8% 0.3% 15.1% 44.8% 45.0% 72.4%
<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.800
96.5% 68.4% 5.8% 62.3% 48.9% 71.2% 80.5%
93.0% 59.0% 7.6% 55.1% 50.9% 70.7% 71.6%
<0.0001 <0.0001 0.0024 <0.0001 0.1227 0.6605 <0.0001 (continued on next page)
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Table 1 (continued) Variable
Age (years)
P value
<80 (n=11,692)
≥ 80 (n = 1,730)
23.9% 79.9% 18% 37.0% 15.5%
53.8% 68.6% 32% 46.1% 12.1%
<0.0001 <0.0001 <0.0001 <0.0001 0.0028
94.8% 63.6% 83.5% 71.6% 15.6% 80.1% 48.0% 20.5%
86.2% 51.3% 69.4% 66.7% 22.2% 68.5% 26.4% 11.0%
<0.0001 <0.0001 <0.0001 0.0003 <0.0001 <0.0001 <0.0001 <0.001
6.0% 3.0% 169 (1.5%) 634 (5.4%) 52 (0.8%) 65 (0.6%) 0.2% 2.3% 0.7% 4.8% 1.0%
17.1% 8.2% 36 (2.1%) 122 (7.1%) 10 (1.1%) 23 (1.3%) 1.7% 4.2% 1.6% 16.1% 2.6%
<0.0001 <0.0001 0.0426 0.005 0.4125 0.0019 <0.0001 <0.0001 0.0010 <0.0001 <0.0001
235 (2.0%) 244 (2.1%) 429 (3.7%) 827 (7.2%)
177 (10.2%) 164 (9.5%) 268 (15.6%) 502 (29.4%)
<0.0001 <0.0001 <0.0001 <0.0001
Diuretics Statins CCB Nitrates Hypoglycemic agents Therapy at 30-day follow-up Aspirin Clopidogrel Statins ACE-I/ARB CCB Beta blockers Referral to rehabilitation program Participating in a rehabilitation program Clinical outcomes In-hospital complications Killip 3 Killip 4 Re MI Post MI angina Stent thrombosis Ischemic stroke Free wall rupture High degree AV block TIA/CVA Acute renal failure Major bleeding Death rates In-hospital death 7-day mortality 30-day mortality 1-year mortality
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers; AV = atrioventricular; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCB = calcium channel blockers; CHF = congestive heart failure; CVA = cerebrovascular accident; ER = emergency room; ICCU = Intensive Cardiac-Care Unit; IQR = interquartile range; LMW = low molecular weight; LVEF = left ventricle ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease; SD = standard deviation; STEMI = ST elevation myocardial infarction; TIA = transient ischemic attack; UF = unfractionated. Dyslipidemia was defined as total cholesterol > 200 mg/dl or patients on lipid lowering therapy.
health status of elderly ACS patients admitted in the late period, they had lower rates of overt CHF symptoms on admission, reflected in the lower Killip class, as well as lower incidence of left ventricular ejection fraction <50%, compared with those in the early period. Throughout the study period, PCIs became more common during hospitalization, and rates of primary PCI more than doubled (10.2% in the early period vs 25% in the late period; p < 0.0001). However, thrombolytic therapy declined according to the trends in guideline recommendations.1,2 Accordingly, there was a marked increment in the usage of guidelinerecommended medications, including dual antiplatelet therapy (42.3% of clopidogrel prescription in the early period vs 83.6% in the late period; p < 0.0001), statins (53.1% vs 91.2%; p < 0.0001), angiotensin converting enzyme inhibitors, β blockers, and hypoglycemic agents across the study years; however, there was a decline in the use of nitrates and digoxin. Increased rates of most guideline-recommended therapy use were
found at 30-day follow-up too, as well as an increment in referral and participation in cardiac rehabilitation programs. Most in-hospital complication rates did not change across the study years, except 3, which improved over the study period (worsening of Killip class to third degree, post-MI angina, and acute renal failure). There was a significant decline in in-hospital, 7-day, and 1-year mortality rates in ACS patients ≥80 years hospitalized in the late compared with the early period. Figure 2 shows a 1-year survival curve, adjusted to the risk factors and previous co-morbidities as in Table 2, which indicates a higher survival probability across 1-year follow-up in the late compared with the early period (HR 1.17, 95% confidence interval 1.15 to 1.61; p = 0.01]. Discussion The current study demonstrated that ACS patients ≥80 years were treated less with guideline-recommended therapies and had
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Table 2 Baseline characteristics, given therapies since admission and clinical outcomes of patients ≥80 years by study period Variable Baseline characteristics Age, (years) (mean ± SD) Men Women Dyslipidemia Hypertension Current smokers Diabetes mellitus Family history of CAD BMI (kg/m2), (mean ± SD) Prior to admission cardiovascular morbidity s/p MI s/p CABG s/p PCI Chronic renal failure PVD s/p CVA/TIA History of CHF Prior concomitant medications (at home) Aspirin Clopidogrel ACE-I/ARB Beta blockers Statins CCB Nitrates Aldosterone receptor antagonist Hypoglycemic agents Diuretics Means of arrival at hospital and time to treatment Mobile ICCU Regular ambulance Private car Time from symptom onset to ER (min) (median, IQR) Time from ER to 1st ward (min) (median, IQR) Door to balloon time (min) (median, IQR) Killip class on admission ≥2 ≥3 LVEF <50% Post admission therapy Reperfusion therapy STEMI, n Reperfusion therapy STEMI Thrombolysis Angio without PCI/urgent CABG Primary PCI Use of IIb/IIIa antagonists Any PCI in STEMI Use of IIb/IIIa antagonists Any PCI in all patients Use of IIb/IIIa antagonists In-hospital therapy Aspirin Clopidogrel Warfarin/oral anticoagulation UF heparin LMW heparin ACE-I/ARB Beta blockers Diuretics
2000–2006 (n = 1,037)
2008–2013 (n = 694)
P value
84.4 ± 4.1 57% 43% 40.9% 73.9% 7.1% 30.0% 4.0% 26.0 ± 4.0
85.0 ± 4.1 57% 43% 75.0% 85.1% 7.1% 38.5% 8.4% 27.4 ± 17.7
0.0002 0.9925 0.9925 <0.0001 <0.0001 0.98 0.0025 0.0002 0.4119
35.7% 12.0% 15.7% 24.2% 14.2% 15.5% 18.6%
41.3% 16.5% 37.0% 30.2% 11.7% 13.6% 18.5%
0.0181 0.0084 <0.0001 0.0057 0.1304 0.2601 0.9759
57.6% 4.7% 46.8% 43.5% 33.1% 31.5% 30.4% 2.0% 18.9% 34.0%
60.0% 17.0% 53.7% 49.7% 58.2% 37.2% 17.5% 4.2% 23.7% 34.2%
0.3356 <0.0001 0.0075 0.0162 <0.0001 0.0215 <0.0001 0.0003 0.0219 0.9537
40.5% 21.0% 31.7% 189 (95–480) 110 (59–198) 71 (43–134)
45.1% 14.5% 33.0% 188 (90–453) 128 (57–229) 88 (45–133)
0.009 0.009 0.009 0.400 0.120 0.270
40.4% 18.6% 73%
28.9% 12.5% 63%
<0.001 <0.001 <0.001
438 18.6% 8.3% 0.1% 10.2% 52.6% 43.0% 52.6% 37.8% 52.6%
233 19.1% 0.8% 0.8% 25.0% 82.0% 46.8% 82.0% 53.9% 82.0%
0.800 <0.0001 <0.0001 <0.0001 <0.01 0.05 0.01 <0.0001 0.01
92.6% 42.3% 7.7% 53.1% 51.4% 68.5% 66.7% 55.4%
93.7% 83.6% 7.5% 58.1% 50.0% 74.1% 78.8% 51.3%
0.4120 <0.0001 0.8741 0.0430 0.5684 0.0128 <0.0001 0.0972 (continued on next page)
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Table 2 (continued) Variable
2000–2006 (n = 1,037)
2008–2013 (n = 694)
P value
53.1% 6.7% 57.8% 9.7%
91.2% 3.5% 33.1% 15.7%
<0.0001 0.0032 <0.0001 0.0018
85.0% 38.1% 56.5% 66.4% 16.5% 64.8% 13.6% 9.2%
88.0% 70.0% 88.0% 67.3% 28.4% 73.9% 31.0% 50.0%
0.0903 <0.0001 <0.0001 0.6916 <0.0001 0.0009 <0.0001 <0.001
19.9% 8.9% 25 (2.4%) 96 (9.4%) 0 (0%) 14 (1.4%) 1.9% 4.6% 1.5% 18.1% 2.4%
13.0% 7.2% 11 (1.6%) 26 (3.8%) 10 (1.4%) 9 (1.3%) 1.3% 3.7% 1.7% 13.1% 2.9%
0.0001 0.2191 0.2276 0.0001 0.0519 0.9099 0.3101 0.4019 0.7634 0.0058 0.5504
120 (11.6%) 112 (10.8%) 177 (17.1%) 327 (31.7%)
57 (8.2%) 50 (7.8%) 85 (13.7%) 118 (26.6%)
0.0238 0.0463 0.0705 0.01
Statins Digoxin Nitrates Hypoglycemic agents Therapy at 30-day follow-up Aspirin Clopidogrel Statins ACE-I/ARB CCB Beta blockers Referral to rehabilitation program Participating in a rehabilitation program Clinical outcomes In-hospital complications Killip 3 Killip 4 Re MI Post MI angina Stent thrombosis Ischemic stroke Free wall rupture High degree AV block TIA/CVA Acute renal failure Major bleeding Mortality rates In-hospital death 7-day mortality 30-day mortality 1-year mortality
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers; AV = atrioventricular; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCB = calcium channel blockers; CHF = congestive heart failure; CVA = cerebrovascular accident; ER = emergency room; ICCU = Intensive Cardiac-Care Unit; IQR = interquartile range; LMW = low molecular weight; LVEF = left ventricle ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease; SD = standard deviation; STEMI = ST elevation myocardial infarction; TIA = transient ischemic attack; UF = unfractionated. Dyslipidemia was defined as total cholesterol > 200 mg/dl or patients on lipid lowering therapy.
worse in-hospital and postdischarge prognosis compared with patients <80 years. Nevertheless, analysis showed raised guidelinerecommended therapy rates (invasive, medical, and rehabilitation) in those ACS patients ≥80 years during 2000 to 2013, with matching progressive improved clinical outcomes. Cardiovascular co-morbidity rates were higher in elderly patients, consistent with previous reports,7,8 which correspond with the high rates of previous concomitant cardiovascular pharmacotherapy found in the elderly group. Another significant difference between the 2 age groups is the longer “door-to-balloon time” in the older age group. This finding is commensurate with previous studies9,10 and might be explained by a longer period of indecision regarding the correct treatment as well as longer procedural delays in the elderly patients. The prehospital delays may be partially explained by atypical symptoms,10 which might make the patients delay recognition of the need to call for help. These delays should alert the medical teams, especially regarding ACS patients ≥80 years who tend to suffer more comorbidities, larger MIs, and a relatively higher mortality risk than their younger counterparts.
Figure 2. A Kaplan–Meier 1-year survival curve of all patients ≥80 years stratified to 2 study periods: patients hospitalized in the early 2000 to 2006 period (lineal line) and late, 2008 to 2013 period (continuous line). p = 0.01 by log-rank test (hazard ratio 1.17, 95% CI 1.15 to 1.61; p = 0.01), adjusted for cardiovascular risk factors, co-morbidities, and hospitalization period.
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Unfortunately, although ACS patients ≥80 years who were hospitalized had larger MIs, lower left ventricular ejection fractions, and higher rates of clinical CHF, they received lower rates of invasive, medical, and rehabilitation guideline– recommended therapies. These findings concur with previous reports.11–16 Late arrival, atypical symptoms, and doctor’s concerns for potential treatment-induced adverse effects and coexisting co-morbid geriatric conditions may contribute to the decreased usage of guideline-recommended therapy even among elderly patients who are eligible for those therapies.10 Increased guideline-recommended therapy use and the corresponding decreasing mortality rate in elderly ACS patients were also demonstrated in previous studies.17–21 Nevertheless, improvement trends in elderly patient outcomes are not absolute. For example, a study that evaluated trends in mortality rates in Croatian ACS patients during 1990 to 2010 demonstrated reduced mortality rate in all age groups except in women >75 years and men >85 years.22 Moreover, in those populations an increment in mortality rates over the period was demonstrated. Those findings may be partially explained by the low access of those populations to guidelinerecommended therapies. Schoenenberger et al23 has recently published a comparison over 3 periods during the years 2000 to 2012 between treatments and outcomes of ACS patients ≥70 years in Switzerland. Both Schoenenberger et al’s and our studies found an increment in previous admission risk factors and co-morbidity rates in elderly patients across the years. Notwithstanding, both studies found reduced mortality and adverse outcome rates across the years that may indicate the significant benefit of using guideline-recommended therapies, even among elderly patients with complex illnesses. We hypothesize that the main explanation for the increment in rates of previous risk factors and co-morbidities is the increased use of guideline-recommended therapies, which enables prolongation of life despite a complex health status. In the past, many patients who suffered from those risk factors and co-morbidities died before they reached their ninth decade. A noteworthy difference between the 2 studies is the higher mortality rate of patients ≥80 years in Schoenenberger et al’s study compared with our current study during the early period (16.3% in octogenarians and 26.5% in nonagenarians in Schoenenberger et al’s study during 2001 to 2004 vs 11.6% in the overall population of patients ≥80 years in our study during 2000 to 2006) or the late period (12.6% in octogenarians and 23% in nonagenarians in Schoenenberger et al’s study during 2009 to 2012 vs 8.2% in the overall population of patients ≥80 years in our study during 2008 to 2013). This difference may be attributed to a shorter duration time between symptom onset to ER admission in our study (189 [90 to 480] minutes without change between the periods) compared with Schoenenberger et al’s study (283 [130 to 765] minutes in the early period and 240 [120 to 637] minutes in the late period). Reduced duration time from symptom onset until ER admission in Schoenenberger et al’s study may provide another possible explanation for the reduction in mortality rates over the years. In our current study, however, no change was demonstrated regarding prehospital delay, thereby strengthening our hypothesis that improved outcome in elderly
patients is mainly derived from the enhanced use of guidelinerecommended therapies. The present study has some limitations. First, our study was based on registry data and therefore may exhibit some limitations (as selection bias). Second, this is a retrospective study, and thus, causal relation between therapy usage rates and outcome trends cannot be associated. Third, the ACSIS survey is a biannual study carried out during the months March to April. This 2-month period might not represent the whole year adequately, and this could influence morbidity and mortality of ACS. In conclusion, ACS patients ≥80 years have a worse prognosis compared with patients <80 years; nevertheless, their clinical outcome improved significantly over the 2000 to 2013 period, which may be well explained by the increment in guideline-recommended therapy usage rates in the elderly patients. Improved alertness and awareness to the need of a high index of suspicion and prompt treatment in elderly patients with ACS, as well as assimilation of the benefits of early invasive reperfusion therapy and pharmacologic and rehabilitation guideline-recommended therapy, may improve the prognosis of this high-risk population. Disclosures The authors state that no conflict of interest exists regarding the possible publication of this article. The corresponding author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso JE, Tracy CM, Woo YJ, Zhao DX, CF/AHA Task Force. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127:529–555. 2. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL, 2012 Writing Committee Members, American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 2012;126:875–910. 3. Kornowski R. The ACSIS Registry and primary angioplasty following coronary bypass surgery. Catheter Cardiovasc Interv 2011;78:537– 539. 4. Segev A, Matetzky S, Danenberg H, Fefer P, Bubyr L, Zahger D, Roguin A, Gottlieb S, Kornowski R. Contemporary use and outcome of percutaneous coronary interventions in patients with acute coronary syndromes: insights from the 2010 ACSIS and ACSIS-PCI surveys. EuroIntervention 2012;8:465–469. 5. O’Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM, Paffenbarger RS Jr, Hennekens CH. An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 1989;80:234–244. 6. Menezes AR, Lavie CJ, Milani RV, Arena RA, Church TS. Cardiac rehabilitation and exercise therapy in the elderly: should we invest in the aged? J Geriatr Cardiol 2012;9:68–75. 7. Devlin G, Gore JM, Elliott J, Wijesinghe N, Eagle KA, Avezum Á, Huang W, Brieger D. Management and 6-month outcomes in elderly and very
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