EJINME-02705; No of Pages 8 European Journal of Internal Medicine xxx (2014) xxx–xxx

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Original Article

Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly) Pablo Herrero-Puente a,⁎, Rocio Marino-Genicio a, Francisco Javier Martín-Sánchez b, Joaquín Vázquez-Alvarez a, Javier Jacob c, Manuel Bermudez d, Pere Llorens e, Òscar Miró f, María José Pérez-Durá g, Victor Gil f, Ana Alonso-Morilla a, representing the members of the ICA-SEMES group (Annex 1) a

Department of Clinical Management of the Emergency Medicine Department, Hospital Universitario Central of Asturias, Group of Investigation in Emergency Medicine-HUCA, Oviedo, Spain Department of Emergency Medicine and Short-Stay Unit, Hospital Clínico San Carlos, Madrid, Spain c Department of Emergency Medicine, Hospital Universitaride Bellvitge, Barcelona, Spain d Department of Management of Geriatric Care, Hospital Monte Naranco, Oviedo, Spain e Department of Emergency Medicine-Short-Stay Unit and Home Hospitalization, Hospital Universitario General de Alicante, Alicante, Spain f Department of Emergency Medicine, Hospital Clinic, IDIBAPS, Barcelona, Spain g Department of Emergency Medicine, Hospital La Fe, Valencia, Spain b

a r t i c l e

i n f o

Article history: Received 23 October 2013 Received in revised form 1 April 2014 Accepted 6 April 2014 Available online xxxx Keywords: Acute heart failure Hospital emergency departments Mortality Very elderly

a b s t r a c t Objectives: To determine the characteristics and prognostic factors of early death in the very elderly with acute heart failure (AHF). Patients and methods: We performed a prospective, observational study of AHF patients attended in Emergency Departments (ED), analyzing 45 variables collected in ED and studying troponin, natriuretic peptides and echocardiographies, not always available in the ED. The patients were divided into 2 groups: nonagenarian (age ≥90 years) and controls (age b 90 years). The study variables were mortality and death or reconsultation to the ED for AHF within 30 days after inclusion. Results: We included 4700 patients (nonagenarians: 520, 11.1%). The 30-day mortality was 21.5% and 8.7% (p b 0.01), respectively with a combined event of 33.3% and 26.7% (p = 0.001). Age ≥90 years was maintained in all the models associated with death (OR: 1.94, CI 95%: 1.40–2.70). In nonagenarians, chronic kidney insufficiency (OR: 2.07, CI95%: 1.16–3.69), severe functional dependence (OR: 2.18, CI95%; 1.30–3.64) and basal oxygen saturation b90% (OR: 1.97, CI95%: 1.17–3.32) and hyponatremia b 135 mEq/L (OR: 1.89, CI95%: 1.05–3.42) were predictive variables of mortality. We observed an association between elevated troponin levels and natriuretic peptide values N 5180 pg/mL and mortality (OR: 4.26, CI95%: 1.83–9.89; and OR: 3.51, CI95%: 1.45–8.48; respectively). Conclusions: The profile of nonagenarians with AHF differs from that of younger patients. Although very advanced age is an independent prognostic factor of mortality, these patients have fewer predictive factors of mortality, being only functional deterioration, basal kidney disease, hyponatremia and respiratory insufficiency on arrival at the ED and probably troponin values and elevated natriuretic peptides. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction In industrialized countries a gradual aging of the population is taking place leading to increasingly more patients of advanced age consulting in emergency departments (ED). Heart failure represents the first cause of hospitalization and consultation in the ED in developed countries among patients over the age of 65 years [1,2], with the prevalence rising with age [1,3]. ⁎ Corresponding author at: Área de Gestión Clínica de Urgencias, Hospital Universitario Central de Asturias, C/Celestino Villamil s/n, 33006 Oviedo, Spain. Tel.: +34 985108137. E-mail address: [email protected] (P. Herrero-Puente).

Patients with a very advanced age are very seldom represented in clinical trials [4] and the prevalence of risk factors and cardiovascular comorbidity [5–12] differs from that of younger patients. Many of these studies have the limitation of being undertaken only in patients attended or admitted to cardiology, internal medicine or geriatric units or are analyses performed in patients included in clinical trials [5] and as such provide only a partial image of this problem since patients with acute heart failure (AHF) are not always admitted to the hospital. The first study of the EAHFE project (Epidemiology Acute Heart Failure Emergency) [13] which was carried out in 10 Spanish EDs demonstrated that more than half of the patients attended in the ED for AHF were

http://dx.doi.org/10.1016/j.ejim.2014.04.002 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

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P. Herrero-Puente et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

entirely managed in these departments: one part of the patients in the short stay units and another part were discharged directly from the ED without admission. Analysis of octogenarian patients in the same series [8] demonstrated that despite different basal characteristics between the patients over 80 years of age and the remaining patients, the mortality was similar, and in contrast to what occurs in most of the previous studies, it was not possible to identify predictive factors of mortality or reconsultation to the ED in this group of subjects over 80 years of age. It is possible that in this study the cut off age of 80 years was not sufficient to identify patients with a clearly increased fragility and who present a different profile from the remaining population since the general advances in health in the last few decades, particularly in the treatment of cardiovascular diseases, have substantially increased the prognosis and survival of the population [14]. Nonetheless, the lack of studies on the management and results of patients with AHF and a very elderly age makes it difficult to use evidencebased medicine to estimate the prognosis of these groups of extreme age. With these precedents the hypothesis of the present study was that very elderly patients with AHF, that is, those with an age ≥ 90 years, have an increased risk of death or reconsultation to the ED in the short-term compared with patients of a younger age, and additionally, it is possible to define the profile of those presenting a greater risk of death or reconsultation.

formula of the Modification of Diet in Kidney Disease (MDRD) study [16]. Data on previous treatment and the management of the patients in the ED were also collected referring to both the treatment administered as well as the destination of the patient following ED care (admission or discharge). The AHF episode was classified based on SBP values as: hypertensive with SBP N 160 mm Hg, normotensive with SBP from 100 to 160 mm Hg, hypotensive without shock with SBP b 100 mm Hg and with no signs of peripheral hypoperfusion and hypotensive with shock with SBP b 100 mm Hg and with signs of peripheral hypoperfusion. On the other hand, some data were not available in all the patients: troponins (not routinely requested in all EDs for all patients with AHF), natriuretic peptides (BNP or NT-proBNP; because not considered urgent in all hospitals) and echocardiography. Left ventricular function was classified based on the left ventricle ejection fraction (LVEF), being depressed when ≤ 45% and preserved when N45%. These three types of data were analyzed separately with the aim of not losing patients from the global analysis due to the absence of any data. 2.3. Follow-up and mortality

2. Patients and methods

The main variables of interest in the follow-up were 30-day mortality following consultation in the ED and the combined variable of mortality or reconsultation for a new episode of AHF within 30 days following inclusion. Follow-up was performed by telephone call and/or consultation of the hospital or primary care clinical report.

2.1. Type of study

2.4. Statistical analysis

The EAHFE project [13] is a prospective, evaluative, multicentric, cohort study without intervention, with consecutive inclusion of all the patients attended for AHF in Spanish EDs. The inclusion criteria was in fulfillment of the Framingham diagnostic criteria. During the design phase of the EAHFE project, the authors considered performing different studies based on data registry. One study was the analysis of very elderly patients (≥ 90 years of age) which was denominated EAHFE-VERY ELDER (EVE study). The study was performed according to the Declaration of Helsinki of 2010 on the ethical principles for medical investigation in humans, and the patients provided informed consent to participate. The complete protocol was approved by the Committees of Ethics and Clinical Investigation of the participating hospitals. Patients without follow-up data at 30 days were excluded The patients were divided into two different groups in which the only difference was age, and this was considered the classifying variable: the group of “nonagenarians” included patients with an age ≥ 90 years and the “control” group was made up of patients of b 90 years.

Absolute and relative frequencies were used for the qualitative variables, and the mean with standard deviation (SD) and the median and interquartile range (IQR) were used for the quantitative variables. For comparisons, the chi-square test was used for the first and the Student's t test was used for the second or the non parametric Mann–Whitney U test was carried out if not fulfilling criteria of normality, being contrasted using the Kolmogorov–Smirnov test. Multivariate logistic regression analysis was performed to control the confounding factors with respect to the effect of age on the objective variables of mortality or combined event, progressively introducing the variables significantly different between the two groups into the model in the bivariate analysis. The independent factors associated with the target variables in both groups were also analyzed by logistic regression. Finally, bivariate analysis was used to determine a possible relationship with the three variables not routinely collected (troponins, natriuretic peptides and the type of left ventricular dysfunction). The odds ratios (OR) adjusted with the confidence interval of 95% (CI95%) were calculated in all the cases. Differences were considered statistically significant with a p value b0.05 and the CI95% of the OR excluded value 1. The SPSS 18.0 statistical program was used for the analyses.

2.2. Demographic and clinical data and complementary studies The demographic data included age and sex. The data on comorbidities included the presence of a history of arterial hypertension (AHT), diabetes mellitus, dyslipidemia, ischemic cardiopathy, valvulopathy, atrial fibrillation (AF), chronic kidney disease (CKD), cerebrovascular disease, chronic obstructive pulmonary disease (COPD), peripheral arteriopathy and previous episodes of AHF. Data related to the basal functional situation included evaluation of basal functional status measured by the Barthel index (BI) [15] and the functional grade of dyspnea according to the New York Heart Association (NYHA). The data of the acute episode included systolic blood pressure (SBP), heart and respiratory rates and basal arterial oxygen saturation by pulsioxymetry and the presence of AF on electrocardiography. The analytical data collected were hemoglobin (anemia was defined according to the WHO recommendations with a hemoglobin value b 12 g/L in women and b13 g/L in men), glucose, creatinine, urea and sodium levels. The estimated glomerular filtration (eGF) rate was calculated with the abbreviated

3. Results Of the 4897 individuals, 197 were excluded due to loss to follow-up. The patients excluded did not present differences compared with those included with respect to the demographic variables, cardiovascular comorbidity and form of presentation of the AHF episode (data not shown). Of the 4700 patients finally analyzed, 520 (11.1%) corresponded to the nonagenarians. Table 1 shows the analysis of all the variables collected in the study, both globally and compared between the two groups. Females predominated in the nonagenarian group, having a lower prevalence of cardiovascular comorbidity, with no differences in the prevalence of the history of chronic kidney disease. Their basal status was worse for both the functional situation and the grade of dyspnea. The group with the oldest age presented a significantly greater percentage of elevated urea levels with diminished eGF. In the acute episode these

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

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Table 1 Basal characteristics of the global patient sample and the two age groups (age less than 90 years and greater than or equal to 90 years). Total N = 4700

Nonagenarian group (≥90 years) N = 520

Control group (b90 years) N = 4180

p

Sociodemographic variables Age (years) [mean (SD)] Female sex [n (%)]

79.5 (10.5) 2679 (57.0)

93.0 (2.5) 382 (73.5)

77.9 (9.9) 2297 (55.0)

b0.0001 b0.0001

Variables of comorbidity Arterial hypertension [n (%)] Diabetes mellitus [n (%)] Dyslipidemia [n (%)] Ischemic cardiopathy [n (%)] Valvulopathy [n (%)] Atrial fibrillation [n (%)] Chronic kidney disease [n (%)] Cerebrovascular disease [n (%)] COPD [n (%)] Peripheral arteriopathy [n (%)] Previous episode of AHF [n (%)]

3917 (83.3) 1975 (42.0) 1853 (39.4) 1413 (30.1) 1286 (27.4) 2275 (48.4) 1152 (24.5) 629 (13.4) 1191 (25.3) 375 (8.0) 2913 (62.0)

438 (84.2) 132 (25.4) 136 (26.2) 126 (24.2) 88 (16.9) 227 (43.7) 129 (24.8) 72 (13.8) 107 (20.6) 21 (4.0) 328 (63.1)

3479 (83.2) 1843 (44.1) 1717 (41.1) 1287 (30.8) 1198 (28.7) 2048 (49.0) 1023 (24.5) 557 (13.3) 1084 (25.9) 354 (8.5) 2585 (61.8)

0.51 b0.0001 b0.0001 0.002 b0.0001 0.022 0.85 0.73 0.008 b0.0001 0.85

Basal situation Basal NYHA III-IV [n (%)] Barthel Index b 60 points [n (%)]

1091 (23.2) 755 (16.1)

153 (29.4) 181 (34.8)

938 (22.4) 574 (13.7)

b0.0001 b0.0001

Treatment prior to consultation in the emergency department Loop diuretics [n (%)] Potassium-sparing diuretics [n (%)] Thiazide diuretic [n (%)] Betablockers [n (%)] ACEI [n (%)] ARABs [n (%)] Calcium antagonists [n (%)] Oral anticoagulation [n (%)] Antiaggregants [n (%)] Digoxin [n (%)]

3130 (66.6) 775 (16.5) 588 (12.5) 1579 (33.6) 1572 (33.4) 1165 (24.8) 1165 (24.8) 1782 (37.9) 1849 (39.3) 895 (19.0)

349 (67.1) 54 (10.4) 62 (11.9) 119 (22.9) 168 (32.3) 119 (22.9) 122 (23.5) 110 (21.2) 256 (49.2) 99 (19.0)

2781 (66.5) 721 (17.2) 526 (12.6) 1460 (34.9) 1404 (33.6) 1046 (25.0) 1043 (25.0) 1672 (40.0) 1593 (38.1) 796 (19.0)

0.92 b0.0001 0.60 b0.0001 0.46 0.24 0.37 b0.0001 b0.0001 0.89

Clinical data of the acute episode Heart rate N 100 bpm [n (%)] Respiratory rate N 20 rpm [n (%)] SBP b 100 mm Hg [n (%)] SatO2 b 90% [n (%)]

1409 (30) 2308 (49.1) 226 (4.8) 1130 (24.0)

159 (30.6) 285 (54.8) 33 (6.3) 181 (34.8)

1250 (29.9) 2023 (48.4) 193 (4.6) 949 (22.7)

0.82 0.002 0.09 b0.0001

Laboratory tests and complementary studies Anemia [n (%)] Glucose (mg/dl) [mean (SD)] Elevated urea [n (%)] eGF b 60 ml/min/1.73 m2 [n (%)] Sodium b 135 mEq/l [n (%)] Atrial fibrillation in the ECG [n (%)] LBB in the ECG [n (%)]

2685 (57.1) 148.4 (68.8) 2376 (50.6) 2656 (56.5) 986 (21.0) 2258 (48.0) 502 (10.7)

299 (57.5) 145.1 (59.6) 306 (58.8) 348 (66.9) 106 (20.4) 233 (44.8) 51 (9.8)

2386 (57.1) 148.9 (69.9) 2070 (49.5) 2308 (55.2) 880 (21.1) 2025 (40.4) 451 (10.8)

0.85 0.26 b0.0001 b0.0001 0.79 0.09 0.49

Treatment and management in the emergency department Conventional oxygen therapy [n (%)] Bolus of loop diuretics [n (%)] Continuous intravenous perfusion of loop diuretics [n (%)] Bolus of loop diuretic followed by perfusion [n (%)] Intravenous nitrates [n (%)] Digoxin [n (%)] Morphine [n (%)] Hospital admission [n (%)]

3620 (77.0) 3949 (84.0) 220 (4.7) 185 (3.9) 965 (20.5) 768 (16.3) 200 (4.3) 3527 (75)

417 (80.2) 444 (85.4) 19 (3.7) 27 (5.2) 96 (18.5) 83 (16.0) 32 (6.2) 435 (83.7)

3203 (76.6) 3505 (83.9) 201 (4.8) 158 (3.8) 869 (20.8) 685 (16.4) 168 (4.0) 3092 (74.0)

0.13 0.61 0.23 0.20 0.18 0.74 0.05 b0.0001

Type of presentation of AHF - Hypertensive [n (%)] - Normotensive [n (%)] - Hypotensive without shock [n (%)] - Hypotensive with shock [n (%)]

1061 (23.2) 3056 (66.8) 180 (3.9) 31 (0.7)

114 (22.6) 329 (65.3) 23 (4.6) 14 (2.8)

947 (23.3) 2727 (67.0) 157 (3.9) 27 (0.7)

0.68

COPD — chronic obstructive pulmonary disease. LVEF — left ventricular ejection fraction. ACEI — angiotensin-converting enzyme inhibitor. ARBs — angiotensin receptor antagonists. SBP — systolic blood pressure, SatO2 — arterial oxygen saturation, eGF — glomerular filtration estimated by the MDRD formula. LBB — left bundle block.

patients also showed greater respiratory insufficiency (SatO2 b 90% and tachypnea). With regard to previous treatment, the nonagenarians used fewer potassium-sparing diuretics, beta-blockers and oral anticoagulants but more frequently received antiaggregants. With respect to the acute episode, these patients presented significantly lower baseline oxygen saturation levels, a higher respiratory rate and a greater deterioration in kidney function. The treatment administered did not differ between the two groups or with respect to the form of presentation of

the AHF. Altogether, 3527 patients (75%) were admitted, with the percentage of patients admitted in the nonagenarian group being higher compared to the control group (83.7% versus 74%, respectively; p b 0.0001). Troponin determinations were obtained in the ED in 2751 patients and NTproBNP in 1882, with previous echocardiographic data available in 2857 patients. These variables were therefore available in 58.5%, 38.7% and 60.8% of the patients, respectively. Positive troponins (51.8%

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

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P. Herrero-Puente et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx Total

Nonagenarians

Control p=0.001

33,3% 27,9%

p=0.001

26,7%

21,5%

10,1%

8,7%

30-day mortality

Death and/or reconsultation at 30 days

identified in the case of the combined variable of mortality and/or reconsultation in the nonagenarian group. The analysis of the subgroups of patients with NT-proBNP determination, troponin values and previous echographic study showed that in the nonagenarians the OR of NP-pro BNP was 3.51 (CI 95%; 1.45–8.48) for mortality and 2.11 (CI 95%: 1.19–3.75) for mortality or reconsultation. For positive troponins the OR was 4.26 (CI95%: 1.83– 9.89) for mortality and 2.48 (CI 95%: 1.61–3.45) for mortality or reconsultation at 30 days; and for preserved LVEF the OR was 0.96 (CI 95%: 0.42–2.18) for 30-day mortality and 0.52 (CI 95%; 0.25–1.08) for mortality or reconsultation at 30 days. In all the cases the variables with significant differences in the bivariate analysis, including kidney function, were introduced in the multivariate model.

Fig. 1. Results in the target variables and the global variables and those of the two study groups.

4. Discussion

versus 37.1%, respectively; p b 0.0001) were more frequently found in the nonagenarian group, while no significant differences were observed in NTproBNP [8895 (SD: 11.34) pg/mL versus 7846 (SD:11,340), respectively; p = 0.21]. Nonagenarians had fewer echographies (42.1% versus 63.1%, respectively; p b 0.0001) and more frequently presented a preserved LVEF (52.6% versus 41.6%, respectively; p = 0.01). The nonagenarian group presented a greater 30-day mortality, and mortality or reconsultation at 30 days was also more frequent (Fig. 1). This association between nonagenarians and a greater 30-day mortality was maintained, independently of the remaining variables analyzed (Table 2). However, the power of the association between age and mortality diminished with the incorporation of the different variables in the model, with a modification of the crude OR of 29.1%. Tables 3 and 4 demonstrate the predictive factors of 30-day mortality and mortality in the two groups. There was a clear difference in the number of predictive factors in the two target variables between the two groups, being lower in the nonagenarian group. In this group, only 4 variables were independently associated with 30-day mortality (having CKD, a BI b 60 points, basal SatO2 b 90% and sodium levels b 35 mEq/L on arrival to the ED), while in the control group age, Barthel b 60 points, tachypnea N20 breaths per minute, SBPb 100 mm Hg, SatO2 b 90%, elevated urea and hyponatremia had an independent relationship with mortality. No independent prognostic factor was

The EVE study is the first carried out in the usual clinical practice in the ED including a population group of very elderly patients and in which more than 15% of the patients in this age group were directly discharged home after ED care. This demonstrates a wider range of very elderly patients with AHF, not only those who were hospitalized [5,17–19], and the results may be extrapolated to the usual ED practice. The population of such an elderly age with AHF is scarcely represented in clinical studies and treatment decision making is based on data from clinical trials and recommendations for younger patients [20,21]. This scarce representation of such an elderly population in the literature makes comparisons with younger series of patients necessary. The mean age of the nonagenarian group in our study was 93 years (SD 2.5), being the highest reported to date and only approached by one of the groups with a mean age of 91.6 years (SD 2.8) studied by Martin-Pfitzenmeyer et al. in 2009 [22]. Nonagenarian patients have a higher probability of death early after the episode of AHF. The influence of advanced age on mortality is maintained once all the possible confounding factors are controlled. Nonetheless, the weight of age on mortality is clearly influenced by other factors, including the basal situation of the patients (basal functional grade for dyspnea and functional deterioration). The influence of these two variables on the mortality of these patients is much greater than the presence of cardiovascular risk factors or cardiovascular disease. It is therefore mandatory to take these variables into account when

Table 2 Relationship between being nonagenarian and the target variables (mortality and the combination of mortality or reconsultation in the emergency department for acute heart failure within 30 days) with sequential adjustment of the confounding factors. Risk of 30-day mortality Sequential adjustment of the model

OR (CI95%)

p

Percentage of modification with respect to previous step

Percentage of modification of the crude OR

No adjustment Adjusted for sex Adjusted for sex and comorbiditya Adjusted for sex, comorbidity and basal situationb Adjusted for sex, comorbidity, basal situation and clinical and analytical parametersc (global model)

2.74 (2.03–3.69) 2.76 (2.04–3.75) 2.74 (2.00–3.74) 2.17 (1.57–3.00) 1.94 (1.40–2.70)

b0.0001 b0.0001 b0.0001 b0.0001 b0.0001

– 0.73 0.73 20.8 10.7

– 0.73 0 20.8 29.2

Sequential adjustment of the model

OR (CI95%)

p

Percentage of modification with respect to previous step

Percentage of modification of crude OR

No adjustment Adjusted for sex Adjusted for sex and comorbiditya Adjusted for sex, comorbidity and basal situationb Adjusted for sex, comorbidity, basal situation and clinical and analytical parametersc (global model)

1.48 (1.15–1.91) 1.52 (1.18–1.97) 1.58 (1.22–2.05) 1.39 (1.06–1.82) 1.32 (1.00–1.72)

0.002 0.004 0.001 0.016 0.047

– 2.7 3.8 12.0 5.0

– 2.7 6.8 6.1 10.8

Risk of readmission or mortality at 30 days

a Comorbidity included in the analysis: diabetes mellitus, dyslipidemia, ischemic cardiopathy, atrial fibrillation, valvulopathy, peripheral arteriopathy and chronic obstructive pulmonary disease. b Basal situation for dyspnea (NYHA III–IV) and basal functional dependence (Barthel Index b 60 points). c Added clinical and analytical parameters: arterial oxygen saturation b90%, reparatory rate N20 breaths per minute, elevated urea and estimated glomerular filtration b60 ml/min.

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

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Table 3 Characteristics of the dead and surviving patients with crude and adjusted OR values (CI95%) in the two groups of patients. Age group ≥90 years Variable

Age group b90 years

Deaths N = 112

Survivors N = 408

Crude OR (CI95%)

Deaths N = 362

Survivors N = 3818

Crude OR (CI95%)

Adjusted OR (CI95%)**

93.4 (2.7) 82 (73.2)

92.9 (2.5) 300 (73.5)

1.09 (0.10–1.18) 1.02 (0.63–1.63)

80.8 (8.5) 193 (53.3)

77.6 (10.0) 2104 (55.1)

1.04 (1.03–1.06) 1.08 (0.87–1.33)

1.03 (1.01–1.06)

Variables of comorbidity Arterial hypertension [n (%)] Diabetes mellitus [n (%)] Ischemic cardiopathy [n (%)] AF [n (%)] Chronic kidney disease [n (%)] Cerebrovascular disease [n (%)] COPD [n (%)] Previous episode of AHF [n (%)]

98 (87.5) 31 (27.7) 35 (31.3) 43 (38.4) 39 (34.8) 14 (12.5) 24 (21.4) 71 (63.4)

340 (83.3) 101 (24.8) 91 (22.4) 184 (45.1) 90 (22.1) 58 (14.2) 83 (20.3) 257 (63.0)

1.49 (0.79–2.80) 1.17 (0.73–1.88) 1.60 (1.01–2.54) 0.77 (0.50–1.18) 1.91 (1.21–3.01) 0.87 (0.47–1.62) 1.07 (0.64–1.79) 1.01 (065–1.58)

291 (80.4) 167 (46.1) 108 (29.8) 166 (45.9) 107 (29.6) 55 (15.2) 110 (30.4) 243 (67.1)

3188 (83.5) 1676 (43.9) 1179 (30.9) 1882 (49.3) 916 (24.0) 502 (13.1) 974 (25.5) 2342 (61.3)

0.82 (0.62–1.09) 1.11 (0.90–1.38) 0.96 (0.76–1.21) 0.88 (0.71–1.09) 1.34 (1.05–1.70) 1.19 (0.88–1.61) 1.29 (1.02–1.64) 1.31 (1.03–1.67)

Basal situation Basal NYHA III–IV [n (%)] Barthel Index b 60 points [n (%)]

38 (33.9) 55 (49.1)

115 (28.2) 126 (30.9)

1.31 (0.83–2.07) 2.48 (1.56–3.93)

128 (35.4) 111 (30.7)

810 (21.2) 463 (12.1)

2.07 (1.64–2.61) 3.23 (2.51–4.15)

1.34 (0.92–1.97) 1.83 (1.23–2.73)

Treatment prior to consultation in the emergency department Diuretics [n (%)] 83 (74.1) 315 (77.2) Beta blockers [n (%)] 28 (25.0) 91 (22.3) ACEI [n (%)] 30 (26.8) 138 (33.8) ARBs [n (%)] 21 (18.8) 98 (24.2) Nitrates [n (%)] 28 (25.0) 92 (22.5) Antiaggregation [n (%)] 57 (50.9) 199 (48.8) Oral anticoagulation [n (%)] 17 (15.2) 93 (22.8)

0.85 (0.52–1.38) 1.17 (0.72–1.90) 0.71 (0.45–1.14) 0.73 (0.43–1.23) 1.15 (0.71–1.87) 1.09 (0.71–1.66) 0.61 (0.34–1.07)

282 (77.9) 109 (30.1) 128 (33.4) 58 (16.0) 76 (21.0) 162 (44.8) 108 (29.8)

2861 (74.9) 1351 (35.4) 1276 (33.4) 988 (25.9) 778 (20.4) 1431 (37.5) 1564 (41.0)

1.26 (0.96–1.66) 0.79 (0.63–1.01) 1.11 (0.89–1.40) 0.55 (0.41–0.74) 1.06 (0.81–1.38) 1.39 (1.11–1.73) 0.62 (0.49–0.79)

0.66 (0.43–1.00)

Clinical data of the acute episode Heart rate N 100 bpm [n (%)] Respiratory rate N20 rpm [n (%)] SBP b 100 mmHg [n (%)] SatO2 b 90% [n (%)]

112 (30.9) 215 (59.4) 45 (12.4) 137 (37.8)

1138 (29.8) 1808 (47.4) 148 (3.9) 812 (21.4)

1.06 (0.84–1.34) 1.84 (1.36–2.50) 3.57 (2.51–5.09) 2.26 (1.80–2.84)

221 (61.0) 107 (44.4) 250 (72.5) 229 (63.3) 113 (31.2) 176 (48.6) 45 (12.4)

2165 (56.7) 959 (36.5) 1820 (50.6) 2079 (54.5) 767 (20.1) 1849 (48.4) 406 (10.6)

1.25 (1.00–1.57) 1.39 (1.07–1.82) 2.57 (2.01–3.29) 1.54 (1.22–1.94) 1.84 (1.45–2.34) 1.01 (0.81–1.26) 1.20 (0.86–1.67)

Sociodemographic variables Age (decimal years) [mean (SD)] Females [n (%)]

68 (60.7) 33 (29.5) 8 (7.1) 51 (45.5)

217 (53.2) 126 (30.9) 25 (6.1) 130 (31.9)

1.55 (0.83–2.87) 0.93 (0.59–1.48) 1.19 (0.52–2.72) 1.84 (1.19–2.83)

Laboratory tests and complementary studies Anemia [n (%)] 72 (64.3) Hyperglycemia [n (%)]a 45 (51.7) Elevated urea [n (%)]b 79 (74.5) eGDF b 60 ml/min/1.73 m2 [n (%)] 85 (75.9) Sodium b 135 mEq/l [n (%)] 32 (28.6) AF in the ECG [n (%)] 41 (36.6) LBB in the ECG [n (%)] 15 (13.4)

227 (55.6) 126 (43.8) 227 (59.6) 263 (64.5) 74 (18.1) 192 (47.1) 36 (8.8)

1.47 (0.95–2.28) 1.38 (0.85–2.23) 1.99 (1.23–3.22) 1.80 (1.10–2.94) 1.84 (1.13–2.98) 0.64 (0.42–0.99) 1.59 (0.84–3.03)

Adjusted OR (CI95%) **

1.45 (0.81–2.60) 2.07 (1.16–3.69)

2.18 (1.30–3.64)

1.97 (1.17–3.32)

1.82 (0.99–3.35) 1.16 (0.60–2.25) 1.89 (1.05–3.42)

1.00 (0.66–1.51) 1.09 (0.74–1.60) 1.18 (0.80–1.73)

1.15 (0.79–1.67) 0.61 (0.40–0.92)

1.86 (1.19–2.92) 2.69 (1.53–4.76) 1,56 (1.07–2.28)

0.96 (0.67–1.38) 1.10 (0.77–1.57) 1.98 (1.31–3.00) 0.90 (0.58–1.38) 1.48 (1.00–2.19)

AF — atrial fibrillation, COPD — chronic obstructive pulmonary disease, NYHA — New York Heart Association, ACEI — angiotensin-converting enzyme inhibitor, ARBs — angiotensin receptor antagonists, PAS — systolic blood pressure, SatO2 — basal oxygen saturation, eGF — estimated glomerular filtration, A F in the ECG — atrial fibrillation in the electrocardiogram performed during stay in the emergency department, LBB — left bundle block. a Only 375 patients were included in the age group ≥90 years and 2871 in those under 90 years in whom glucose determination was performed. b Only 478 patients were included in the group ≥90 years and 3944 in the group under 90 years in whom urea values were determined.

evaluating the most adequate management of these patients and their final destination of hospital discharge or admission [23]. Basal functional deterioration is little evaluated as a prognostic factor in the literature, although some studies have demonstrated a correlation with early, 6-month or one-year mortality [8,11,19,22,24] in hospitalized populations. The BI assesses 10 aspects of functional dependence which, on occasions, make their performance difficult in patients during attendance in the ED. However, taking into account the prognostic importance of this index, systemic use is of great utility. This functional dependence is an important prognostic conditioner, and remained an independent predictive factor in the cohort of greatest age, with the highest OR. These very elderly patients present differentiated characteristics compared to younger subjects, having already been observed in the analysis performed in another of our registries of octogenarian patients [8]. One common characteristic in this type of population is the predominance of females, with a growing trend with the increase in age of the population studied. The percentage of female predominance in our study was nearly 75%, being greater than that in other studies published [5,17,22,25], translating the greater survival of women. This predominance of female sex in AHF is associated with the presence of another important risk factor, AHT. Since our series includes the most elderly

patients studied in the literature, the prevalence of this risk factor was clearly superior to the 60 to 75% reported [5,17,22,25]. The inclusion of patients discharged from the ED may make this population have a lower risk of mortality than when only admitted patients are analyzed. Nonagenarians have a lower prevalence of diabetes, dyslipidemia and ischemic cardiopathy than younger patients, similar to other series [17,22,23]. However, there are some discrepancies with regard to the appearance of other diseases such as AF or COPD in which some studies have not shown a clear pattern of appearance based on age groups while being less prevalent in the nonagenarians in our study. With regard to kidney function no differences were observed between the two age groups in the prevalence of the history of CKD, while differences were found in the deterioration of glomerular filtration in the acute phase of the episode. This may be due to underdiagnosis of CKD in very elderly patients with the use of creatinine levels for the diagnosis or the importance of the kidney–heart relationship as a physiopathologic aspect in the decompensation observed in heart failure. This aspect is an important line of investigation in this population using recently described biomarkers such as NGAL or cistatin C [39,40]. Four independent predictive factors of early mortality have been identified in this advanced age group: history of CRF, basal functional dependence, respiratory insufficiency on arrival to the ED (basal oxygen

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

6

Nonagenarian group (≥90 years)

Control group (b90 years)

Deaths or reconsultation N = 173

Supervisors without reconsultation N = 337

Crude OR (CI 95%)

Sociodemographic variables Age (decimal years) [mean (SD)] Female sex [n (%)]

93.2 (2.7) 127 (73.4)

92.9 (2.5) 248 (73.6)

1.05 (0.98–1.13) 1.01 (0.67–1.53)

Variables of comorbidity Arterial hypertension [n (%)] Diabetes mellitus [n (%)] Ischemic cardiopathy [n (%)] AF [n (%)] Chronic kidney disease [n (%)] Cerebrovascular disease [n (%)] COPD [n (%)] Previous episode of AHF [n (%)]

155 (89.6) 52 (30.1) 54 (31.2) 64 (37.0) 49 (28.3) 22 (12.7) 35 (20.2) 112 (64.7)

274 (81.3) 80 (23.7) 70 (20.8) 161 (47.8) 77 (22.8) 49 (14.6) 70 (20.8) 209 (62.0)

2.06 (1.17–3.65) 1.39 (0.92–2.09) 1.74 (1.15–2.64) 0.64 (0.44–0.94) 1.34 (0.88–2.03) 0.86 (0.50–1.48) 0.97 (0.61–1.53) 1.07 (0.73–1.58)

1.80 (0.89–3.67)

Basal situation Basal NYHA III–IV [n (%)] Barthel Index b 60 points [n (%)]

61 (35.3) 68 (39.3)

89 (26.4) 110 (32.6)

1.59 (1.06–2.39) 1.47 (0.98–2.19)

1.32 (0.78–2.21)

Treatment prior to consultation in the emergency department Diuretics [n (%)] 128 (74.0) Beta blockers [n (%)] 42 (24.3) ACEIs [n (%)] 47 (27.2) ARBs [n (%)] 40 (23.1) Nitrates [n (%)] 49 (28.3) Antiaggregation [n (%)] 90 (52.0) Oral anticoagulation [n (%)] 29 (16.8)

261 (77.4) 76 (22.6) 118 (35.0) 76 (22.6) 67 (19.9) 162 (48.1) 78 (23.1)

0.84 (0.55–1.30) 1.11 (0.72–1.71) 0.69 (0.46–1.04) 1.04 (0.67–1.60) 1.61 (1.05–2.46) 1.18 (0.82–1.71) 0.67 (0.42–1.08)

Clinical data of the acute episode Heart rate N 100 bpm [n (%)] Respiratory rate N20 rpm [n (%)] SBP b 100 mmHg [n (%)] SatO2 b 90% [n (%)]

52 (30.1) 100 (57.8) 9 (5.2) 72 (41.6)

102 (30.3) 178 (52.8) 24 (7.1) 106 (31.5)

0.97 (0.65–1.45) 1.36 (0.81–2.29) 0.72 (0.33–1.60) 1.56 (1.07–2.29)

Laboratory tests and complementary studies Anemia [n (%)] 105 (60.7) Hyperglycemia [n (%)]a 70 (53.8) b Elevated urea [n (%)] 110 (66.7) eGF b 60 ml/min/1.73 m2 [n (%)] 121 (69.9) Sodium b 135 mEq/l [n (%)] 45 (26.0) AF in the ECG [n (%)] 64 (37.0) LBB in the ECG [n (%)] 21 (12.1)

187 (55.5) 98 (41.7) 190 (60.7) 219 (65.0) 58 (17.2) 163 (48.4) 29 (8.6)

1.26 (0.87–1.84) 1.63 (1.06–2.51) 1.30 (0.87–1.92) 1.27 (0.85–1.91) 1.69 (1.08–2.63) 0.62 (0.42–0.91) 1.46 (0.81–2.65)

Variable

Adjusted OR (CI 95%)**

1.32 (0.70–2.50) 0.97 (0.55–1.73)

1.59 (0.83–3.04)

1.30 (0.78–2.16)

1.52 (0.93–2.47)

1.29 (0.73–2.29) 0.83 (0.46–1.49)

Deaths or reconsultation N = 1114

Supervisors without reconsultation N = 2991

Crude OR (CI 95%)

Adjusted OR (CI 95%)**

78.7 (9.3) 510 (45.8)

77.5 (10.2) 1339 (44.8)

1.01 (1.01–1.02) 1.04 (0.91–1.20)

1.01 (1.00–1.02)

938 (84.2) 529 (47.5) 367 (32.9) 540 (48.5) 303 (27.2) 155 (13.9) 338 (30.3) 754 (67.7)

2479 (82.9) 1284 (42.9) 887 (29.7) 1474 (49.3) 698 (23.3) 391 (13.1) 725 (24.2) 1779 (59.5)

1.11 (0.92–1.33) 1.21 (1.05–1.39) 1.17 (1.07–1.35) 0.97 (0.84–1.11) 1.23 (1.05–1.44) 1.08 (0.88–1.31) 1.37 (1.17–1.59) 1.45 (1.25–1.69)

304 (27.3) 209 (18.8)

607 (20.3) 347 (11.6)

1.65 (1.40–1.94) 1.91 (1.58–2.31)

1.31 (1.07–1.61) 1.66 (1.32–2.09)

875 (78.5) 391 (35.1) 399 (35.8) 254 (22.8) 254 (22.8) 466 (41.8) 418 (37.5)

2212 (74.0) 1047 (35.0) 981 (32.8) 771 (25.8) 581 (19.4) 1098 (36.7) 1229 (41.1)

1.34 (1.13–1.60) 1.01 (0.88–1.17) 1.16 (1.00–1.34) 0.86 (0.73–1.01) 1.23 (1.05–1.46) 1.26 (1.09–1.45) 0.87 (0.75–1.00)

1.10 (0.87–1.39)

308 (27.6) 528 (47.4) 71 (6.4) 281 (25.2)

920 (30.8) 1448 (48.4) 116 (3.8) 649 (21.7)

0.87 (0.74–1.01) 1.10 (0.93–1.33) 1.70 (1.25–2.30) 1.22 (1.04–1.43)

665 (59.7) 285 (37.5) 637 (60.4) 653 (58.6) 283 (25.4) 505 (45.3) 128 (11.5)

1673 (55.9) 754 (36.8) 1396 (49.5) 1608 (53.8) 578 (19.3) 1485 (49.6) 314 (10.5)

1.17 (1.02–1.35) 1.03 (0.87–1.23) 1.55 (1.35–1.80) 1.24 (1.08–1.43) 1.42 (1.21–1.67) 0.85 (0.74–0.98) 1.12 (0.90–1.39)

1.08 (0.90–1.29) 0.89 (0.71–1.10) 0.87 (0.70–1.08) 1.42 (1.17–1.72) 1.27 (1.03–1.56)

1.14 (0.91–1.44) 1.22 (1.01–1.47)

1.64 (1.13–2.38) 1.12 (0.91–1.37)

1.03 (0.86–1.24) 1.50 (0.22–1.85) 0.91 (0.73–1.13) 1.35 (1.10–1.65) 0.81 (0.67–0.97)

AF — atrial fibrillation, COPD — chronic obstructive pulmonary disease, NYHA — New York Heart Association, ACEI — angiotensin-converting enzyme inhibitor, ARBs — angiotensin receptor antagonists, SBP — systolic blood pressure, SatO2 — basal arterial oxygen saturation, eGF — estimated glomerular filtration, AF in the ECG — atrial fibrillation in the electrocardiogram performed during care in the emergency department, LBB — left bundle block. a Only 375 patients were included in the age group ≥90 years and 2871 in those under 90 years in whom glucose determination was performed. b Only 478 patients were included in the group ≥90 years and 3944 in the group under 90 years in whom urea values were determined.

P. Herrero-Puente et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

Table 4 Characteristics of the dead patients and/or those who reconsulted and those who did not with the crude and adjusted OR values (CI 95%) in the two groups of patients.

P. Herrero-Puente et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

saturation b90%) and hyponatremia in the acute episode, the latter possibly contributing to the use of some type of treatment such as aquaretic drugs [26]. This is in contrast with the 8 independent predictive factors found in the age group of b90 years. Very elderly patients probably have a physiopathological substrate different from that of the lower age group, conditioning their mortality and making it difficult to find prognostic factors [27] among those usually determined. This aspect does not occur in patients of a younger age [8,11,28]. One of the variables which was demonstrated to be predictive of the combined variable of mortality and/or reconsultation in the group of nonagenarians was the use of intravenous nitrates. This is because their use is a priority in patients with acute hypertensive heart failure who have lower mortality and greater reconsultation rates. This aspect acts as a confounding factor and conditions the relationship between intravenous nitrates and this variable. The use of NT-proBNP and troponins is not generalized in the evaluation of patients with this disease in the ED, and their utility in elderly patients and in the ED with regard to diagnosis as well as prognosis has not been clearly described in the literature [29]. Both variables present an independent prognostic capacity in the two age groups, controlling other variables which influence their levels such as kidney function, although they were used in less than half of the samples analyzed. This would help to identify a group of lower risk of mortality using a cut off of 5180 pg/dL for NT-proBNP. This aspect has already been reported in a similar younger population [30], although their availability in the ED does not condition the short-term prognosis of the patients since they are not used by the attending physicians as conditioners of the treatment to be administered [31]. Similarly, the presence of positive troponins in the acute episode without an acute coronary event is very significantly associated with early death [32]. Thus, generalized use should be recommended, especially in very elderly patients in whom the number of prognostic factors is lower, although a specific study in this very elderly population is necessary to confirm these findings. Another prognostic factor in heart failure, particularly of long-term, and with the greatest amount of evidence in the literature, is the presence of systolic dysfunction [17,33], overall in the young population. In a study by Satomura et al. [34], elderly patients admitted with AHF were analyzed and compared according to the type of dysfunction. No differences were found between the two groups based on the type of dysfunction presented, although the size of the sample was very small. In our series the use of echocardiography was very scarce among the elderly patients, having been performed in only 41.9% of the nonagenarians, with predomination of the preserved ejection fraction, similar to what has been previously published [34,35]. This low percentage of elderly patients with echocardiographic study (common occurrence in patients with AHF attended in Spanish ED [36]) does not allow conclusions to be made in our study and hinders the standardization of treatment based on the type of ventricular dysfunction. This is one of the clearly differentiated aspects of our populational stratum, while in young patients admitted for an episode of AHF it is usual to know the type of dysfunction thereby conditioning the basal therapeutic management. In patients attended in the ED and, overall, those of more elderly age, treatment-related decisions are made without knowledge of the type of dysfunction presented. On comparing the previous treatment of the patients included in the study, we observed that beta blockers and potassium-sparing diuretics were used less frequently in the elderly population. This is a constant variable in the studies performed in this population [17,33] and is probably due to the little scientific evidence available on the use of these substances in patients of these very elderly ages as well as the greater probability of complications derived from their use, such as hyperpotassemia in the case of potassium-sparing diuretics [37]. As shown in other studies it is also of note that there is a reduction in the prescription of oral anticoagulants with age [38]. Thus, in our series more than half of the elderly with AF did not receive this therapy,

7

despite knowing the greater benefits in survival and a reduction in embolic risk with no repercussion on functional status. There were no differences between groups in the treatment of the acute episode. This is because the management of AHF in the ED is based on the form of presentation, and in this respect there are no differences according to age. This study has limitations. First, the diagnosis was clinical, and, although the Framingham criteria have demonstrated a good specificity in the diagnosis of AHF, cases with another pathology may have been included. Second, despite the consecutive inclusion design of the study and the high commitment and experience of the participating centers, there may have been some bias of inclusion toward patients with more demonstrative forms and with a clearer symptomatology in detriment to milder forms of presentation. Third, some variables were not collected in all the patients. The most evident case, as discussed previously, is that of the troponins, the natriuretic peptides and echocardiography. To avoid this problem we decided to analyze the patients in whom these variables were available separately. In conclusion, the profile of very elderly patients with AHF is different from that of younger patients, but the presentation of the acute episode is similar and as such there are no differences in their management in the ED. Very elderly age is an important and independent prognostic factor of mortality, but it is not the only conditioning factor since other aspects may also have influence. It is difficult to find prognostic factors of early mortality in very elderly patients, with only functional deterioration and basal kidney disease as well as hyponatremia and respiratory insufficiency during the acute event being considered as such. In view of the scarcity of prognostic markers, the incorporation of both NT-proBNP and troponins should be considered since they provide important prognostic information which would justify their use in patients with a very elderly age. Learning points • Very elderly patients with acute heart failure have fewer prognostic markers than younger patients. • In very elderly patients, mortality does not depend only on advanced age. • Severe functional dependence is one of the clinical variables with the greatest predictive capacity and also presents great interaction with age. • In very elderly patients, probably NTproBNP and troponin biomarkers could be of value in determining prognosis. The NTproBNP and troponin biomarkers probably have prognostic value in very elderly patients. Conflict of interests The authors state that they have no conflicts of interest. Acknowledgments This study was carried out within the projects PI10/01918 and PI11/ 01021 of the Instituto de Salud Carlos III and received financial support from Fondos FEDER. The Group of Investigation in Emergency Medicine “Emergency care: processes and diseases” of the IDIBAPS receives financial support from the Generalitat de Catalunya for Consolidated Groups of Investigation (GRC 2009/1385). Members of EAHFE Registry of the Work Group ICA-SEMES. Marta Fuentes (University Hospital of Salamanca). José Vallés (La Fe Hospital of Valencia). Víctor Gil, Rafael Perelló (Clinic Hospital of Barcelona). José Pavón, Ana Bella Álvarez (Dr. Negrín Hospital of Las Palmas of Gran Canaria). Antonio Noval (Insular Hospital of Las Palmas of Gran Canaria). José M. Torres (Reina Sofía Hospital of Córdoba). Maria Luisa López-Grima (Dr. Peset Hospital of Valencia). Alfons Aguirre (The Mar Hospital of Barcelona). Helena Sancho (Valme Hospital of Sevilla). Antonio Giménez, José Miguel Franco (Miguel Servet Hospital of

Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002

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Please cite this article as: Herrero-Puente P, et al, Characteristics of acute heart failure in very elderly patients — EVE study (EAHFE very elderly), Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.04.002