De novo acute heart failure: Clinical features and one-year mortality in the Spanish nationwide Registry of Acute Heart Failure

Med Clin (Barc). 2019;152(4):127–134

www.elsevier.es/medicinaclinica

Original article

De novo acute heart failure: Clinical features and one-year mortality in the Spanish nationwide Registry of Acute Heart Failure夽 Jonathan Franco a,∗ , Francesc Formiga b , Xavier Corbella b,c , Alicia Conde-Martel d , Pau Llácer e , Pablo Álvarez Rocha f , Gabriela Ormaechea Gorricho f , José Satué g , Llanos Soler Rangel h , Luis Manzano i , Manuel Montero-Pérez-Barquero j , on behalf of the RICA Research Group♦ a

Departamento de Medicina Interna, Hospital Universitario Quirón Dexeus, Barcelona, Spain Departamento de Medicina Interna, Hospital Universitario Bellvitge, Hospitalet de Llobregat, Barcelona, Spain c Cátedra Hestia en Atención Social y Sanitaria, Facultad de Medicina y Ciencias de la Salud, Universitat Internacional de Catalunya, Barcelona, Spain d Departamento de Medicina Interna, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Gran Canaria, Spain e Departamento de Medicina Interna, Hospital de Manises, Valencia, Spain f Unidad Multidisciplinaria de Insuficiencia Cardiaca, Hospital de Clínicas Dr. Manuel Quintela, Montevideo, Uruguay g Departamento de Medicina Interna, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain h Departamento de Medicina Interna, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain i Departamento de Medicina Interna, Hospital Universitario Ramón y Cajal, Universidad de Alcalá (IRYCIS), Madrid, Spain j Departamento de Medicina Interna, IMIBIC/Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain b

a r t i c l e

i n f o

Article history: Received 14 March 2018 Accepted 24 May 2018 Available online 8 January 2019 Keywords: Acute heart failure New onset heart failure Clinical characteristics Prognosis Left ventricular ejection fraction

a b s t r a c t Introduction and objectives: Acute heart failure (AHF), can occur as decompensated chronic heart failure (HF) or as a first episode, “new onset”. The aim of this study was to analyse the clinical characteristics and prognosis at one-year in a cohort of patients with new onset AHF. Methods: Prospective observational study of 3550 patients with AHF. We compared patients with new onset HF with the others. Restricting the analysis to new onset AHF patients, we analysed the clinical characteristics, readmissions, mortality and impact of left ventricular ejection fraction on the prognosis. Results: A total of 1105 (31%) patients fulfil the criteria for new onset AHF. These patients versus the rest, were younger, had a higher aetiology of hypertension and preserved left ventricular ejection fraction, less global comorbidity and better baseline overall functional status. After one year, mortality in new onset HF was less than chronic decompensated HF (15 vs. 27%; p < 0.001; respectively). Multivariate analysis showed a correlation between mortality and higher global comorbidity (hazard ratio – HR – 1.11), renal failure (HR 1.73), higher prescription of antialdosteronics and antiaggregant (HR 2.13; 1.8; respectively). Left ventricular ejection fraction was unrelated to mortality. Conclusions: New onset AHF shows a clinical profile and prognosis different to that of chronic decompensated HF. Higher comorbidity, renal function and treatment post-discharge predict a higher risk of mortality. ˜ S.L.U. All rights reserved. © 2018 Elsevier Espana,

夽 Please cite this article as: Franco J, Formiga F, Corbella X, Conde-Martel A, Llácer P, Álvarez Rocha P, et al. Insuficiencia cardiaca aguda de novo: características clínicas y ˜ en el Registro Espanol ˜ de Insuficiencia Cardiaca Aguda. Med Clin (Barc). 2019;152:127–134. mortalidad al ano ∗ Corresponding author. E-mail address: [email protected] (J. Franco). ♦ The names of the components of the RICA research group are included in the Appendix A. ˜ S.L.U. All rights reserved. 2387-0206/© 2018 Elsevier Espana,

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J. Franco et al. / Med Clin (Barc). 2019;152(4):127–134

Insuficiencia cardiaca aguda de novo: características clínicas y mortalidad al ˜ en el Registro Espanol ˜ de Insuficiencia Cardiaca Aguda ano r e s u m e n Palabras clave: Insuficiencia cardiaca aguda Insuficiencia cardiaca de novo Características clínicas Pronóstico Fracción de eyección ventricular izquierda

Introducción y objetivos: La insuficiencia cardiaca aguda (ICA) puede suceder como una descompensación de una IC crónica o como un primer episodio “de novo”. Nuestro objetivo fue analizar las características ˜ en una cohorte de ICA de novo. clínicas y el pronóstico al ano, Métodos: Estudio observacional y prospectivo de 3550 pacientes con ICA. Se analizan las características clínicas, la fracción de eyección ventricular izquierda, los reingresos y factores asociados a mayor ˜ de los pacientes con ICA de novo y se comparan con el resto. mortalidad al ano Resultados: Un total de 1105 (31%) pacientes, presentaron ICA de novo. Este grupo fue más joven, con mayor etiología hipertensiva y fracción de eyección ventricular izquierda preservada, mejor estado fun˜ de seguimiento, la mortalidad fue menor cional y menor comorbilidad que el resto de la cohorte. Al ano en ICA de novo frente a IC crónica descompensada (el 15 vs. el 27%; p < 0,001). En el análisis multivariante, los factores asociados a mortalidad en ICA de novo fueron: comorbilidad global (hazard ratio –HR – 1,11), insuficiencia renal (HR 1,73), prescripción de antialdosterónicos y antiagregantes (HR 2,13; 1,8; respectivamente). No se objetivaron diferencias pronósticas en cuanto a la fracción de eyección ventricular izquierda. Conclusiones: Los pacientes con ICA de novo tienen un perfil clínico diferente a la IC crónica descompen˜ en ICA de novo sada, con un mejor pronóstico. Los principales factores predictores de mortalidad al ano fueron la comorbilidad global, la función renal y el tipo de tratamiento al alta hospitalaria. ˜ S.L.U. Todos los derechos reservados. © 2018 Elsevier Espana,

Introduction Heart failure (HF) is a clinical syndrome with multi-organ involvement, whose prevalence and incidence is increasing in developed countries.1–3 Despite therapeutic advances, patients with HF have a high rate of readmissions and short to medium term mortality.4,5 From a physiopathological and clinical perspective, patients with HF are classified into two main groups, based on the left ventricular ejection fraction (LVEF): HF with reduced LVEF (HFtEF: <40%) and preserved LVEF (HFpEF: ≥50%). Recently, the European Society of Cardiology modified the HF classification, adding the improved LVEF group (HFiEF: 40–49%), knowledge of which is still limited.6 Acute HF (AHF) can occur as a result of previously known decompensated chronic HF or a first event, called de novo AHF,7 which constitutes about a third of cases.8–10 Some studies have evaluated the clinical profile and prognosis of patients with de novo AHF, although few have studied a cohort within usual clinical practice in exclusively Internal Medicine services.11,12 The objectives of the present study were to evaluate the clinical profile and prognosis of patients with de novo AHF, comparing that data with data from those patients who have acute decompensation of a chronic HF; analyse factors associated with de novo AHF mortality in the medium term and evaluate the prognostic impact of LVEF. Method Study participants In 2015 Franco et al., Described the clinical characteristics and early mortality (90 days) of de novo AHF in Internal Medicine Services in Spain.13 This article is a continuity of that study, but with a significantly expanded sample and a longer follow-up. All the patients included in the Spanish Registry of Acute Heart Failure (RICA - for its acronym in Spanish) from 2008 to 2016 were analysed. RICA is a prospective and multicentre registry, in which 52 hospitals of different complexity participate.14 It includes patients aged ≥50 years, admitted to the Internal Medicine service

because of AHF, according to the European Society of Cardiology diagnostic criteria.6 RICA excludes patients who die during hospital admission, such that the mortality per year rate does not include these patients. In order to determine patients’ reasons for hospital discharge and their clinical situation at that time, follow-up visits were made at three and 12 months. When patients did not attend their control visits, the patients (or their relatives) were contacted. Admissions after initial admissions were coded as readmissions. The Córdoba Reina Sofía university hospital Clinical Research Ethics Committee approved the protocols for data collection, and all the patients gave their informed consent to participate. Variables The data was registered through a website (https://www. registrorica.org) that contained the main database, which researchers could access with a personal password. The registry included: sociodemographic data, comorbidities (Charlson Index), baseline functional status for basic activities of daily living (Barthel Index) and data at clinical admission: blood pressure, heart rate, body mass index (BMI), trigger factors and the prescription of medications. With regard to clinical severity, the functional class was used through the New York Heart Association (NYHA) scale. Regarding the causes of death, deaths from all causes and those due to cardiovascular causes were analysed. The LVEF evaluation was performed using 2-D echocardiography and possible alterations in the electrocardiogram were analysed. Analytical determinations included blood count, renal function, glucose, uric acid, troponins and N-terminal prohormone brain natriuretic peptide (NT-proBNP), whenever possible. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation and chronic kidney disease was considered when the glomerular filtration rate was less than 60 ml/min/1.73 m2 . Groups Patients were divided into two groups according to whether they presented de novo AHF or decompensation of a chronic HF. Furthermore, patients with de novo AHF were categorised

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into three currently accepted subgroups according to LVEF and analysed: at <40% reduced (HFtEF), 40–49% improved (HFiEF) and ≥50% preserved (HFpEF).

Objectives The primary objectives were to analyse and compare clinical characteristics, rate of readmissions and mortality per year, between the de novo HF group and the decompensated chronic HF. Secondary objectives were to analyse possible factors associated with mortality in the de novo group and the prognostic impact of LVEF.

Statistical analysis A descriptive analysis of the population under study was carried out using mean and standard deviation for the quantitative variables and percentage for the categorical variables. The baseline characteristics of the groups were compared using the Anova and Chi-square tests for quantitative and categorical variables respectively. Mortality and readmissions were analysed at one year of follow-up, and the cumulative episodes curves were used to observe the prognostic differences between the groups using the Kaplan–Meier method. A multivariate logistic regression analysis was performed for mortality using the conditional backward method for the variables that showed a statistically significant relationship with the probability of readmission or death in the bivariate analysis. All variables were included in the multivariate analysis, except for those with more than 20% of lost values (C-reactive protein, urate, NT-proBNP, troponin). The level for statistical significance was set at p < 0.05. The Statistical Package for Social Sciences (SPSS) programme (IBM SPSS version 21.0 Armonk, NY) was used to analyse the data.

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Episodes at three and 12 months after discharge Table 2 shows the duration of hospital stays and re-entry and mortality rates at three and 12 months. Hospital stay was significantly greater in the decompensated chronic HF group compared to patients with de novo AHF (11 days vs. 9.4 days; p < 0.001). Of the total of 3550 patients, 331 (9.8%) died at three months and 818 (23%) at 12 months. Mortality from any cause was approximately twice as high in patients with decompensated chronic HF compared to the de novo AHF group, both at three months and at 12 months. In both groups, death by cardiovascular causes prevailed over non-cardiovascular. Rate of readmissions at three and 12 months of survival were also significantly higher in the decompensated chronic HF group compared to de novo AHF, regardless of the cause. Fig. 1 shows the Kaplan–Meier mortality and readmission curves, due to all causes and cardiovascular causes, at 12 months for both groups. Likewise, Fig. 2 shows the combined mortality/readmission rates for both groups at 12 months. Factors associated with mortality in de novo acute heart failure Table 3 shows the univariate and multivariate analysis of factors associated with mortality at three and 12 months after hospital discharge due to a de novo AHF. The variables independently associated with increased mortality were: presenting a greater general comorbidity (hazard ratio [HR] = 1.11, 95% confidence interval [95% CI] 1.04–1.18; p = 0.02), poor renal function at admission (HR = 1.73; 95% CI, 1.38–2.16; p < 0.001), antialdosterone prescription at discharge (HR = 2.13; 95% CI, 1.52–2.99; p < 0.001). Conversely, the following were associated with lower mortality: a higher BMI (HR = 0.94; 95% CI, 0.91–0.97; p < 0.001), a better baseline function (HR = 0.98; 95% CI, 0.97–0.99; p < 0.001), or a prescription at discharge of: ACEI/ARB HR = 0.70; 95% CI, 0.50–0.98; p = 0.038), beta blockers (HR = 0.57; 95% CI, 0.41–0.79; p < 0.001), and/or statins (HR = 0.62; 95% CI, 0.44–0.87; p = 0.006).

Results Baseline characteristics A total of 3550 patients were analysed for the 2008–2016 period, with an average age of 79.3 ± 8.4 years, of whom 1881 (53%) were female. De novo AHF was present in 1105 (31%) patients. The baseline characteristics of both groups at admission can be seen in Table 1. The comparison between both groups showed that patients admitted for de novo AHF were younger, had a lower overall comorbidity, better functional status, higher proportion of HF due to hypertension, and a lower ischaemic and valvular aetiology. Also, in the emergency department, patients de novo AHF had a lower proportion of advanced functional class (NYHA III–IV) and the reason for admission was to a lesser extent a diagnosis of acute pulmonary oedema. The group of patients with de novo AHF presented atrial fibrillation with rapid ventricular response as the main triggers, followed by respiratory infections and acute coronary syndrome, whereas in the decompensated chronic HF group, respiratory infections predominated, poor adherence to treatment and the appearance of certain comorbidities such as anaemia or renal failure. Patients with de novo AHF received, as treatment at discharge, a higher prescription of inhibitors/blockers of the renin angiotensin axis (ACEI/ARAII) while prescriptions for antialdosteronics, statins and/or digoxin was lower in this group.

De novo acute heart failure according to its left ventricular ejection fraction Table 4 shows the comparison of the baseline clinical characteristics of the 1105 patients with de novo AHI according to their LVEF. Patients with HFtEF were younger, predominantly male and of ischaemic aetiology, with worse functional class, and had a higher prescription of beta-blockers and antialdosteronics at discharge. In contrast, patients with HFpEF were older, predominantly female and of hypertensive aetiology, with greater presence of atrial fibrillation and better functional class. The group with HFiEF presented shared similarities with the other two groups, in general terms, they were similar to the HFpEF group in age, presence of atrial fibrillation and NYHA I-II functional class, but by contrast, they shared with the HFtEF group a predominance of being male, a greater proportion of ischaemic aetiology, and a greater prescription of antiaggregants. Regarding readmission and mortality rates, patients with HFpEF showed a tendency to longer survival and a higher rate of readmissions compared to the other two groups; the HFrEF group showed the worst prognosis, although without reaching statistical significance. Discussion The analysis of a cohort of patients hospitalised in the RICA showed that up to a third of the admissions were due to an episode of de novo AHF. This percentage concurs with the range of other

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Table 1 Baseline characteristics of patients with de novo acute heart failure versus decompensated chronic HF. Total (n = 3550)

De novo (n = 1105)

Decompensated chronic (n = 2445)

Age (years), mean ± SD Sex male (%) BMI kg/m2 , mean ± SD

79.3 (8.4) 1669 (47%) 29.3 (10.1)

78.8 (8.9) 534 (48%) 29.1 (5.4)

79.6 (8.2) 1135 (46%) 29.3 (11.6)

p

Aetiology of HF (%) Ischaemic Hypertensive Valvular Others

958 (27%) 1359 (39%) 621 (18%) 563 (16%)

265 (24%) 465 (42%) 132 (12%) 240 (22%)

693 (29%) 894 (37%) 489 (20%) 323 (13%)

0.003 0.006 <0.001 <0.001

Precipitating factor of the AHF (%) ACS Hypertensive emergency Rapid atrial fibrillation Transgression Respiratory infection Others Diabetes mellitus (%) Arterial hypertension (%) COPD (%) Atrial fibrillation (%) Charlson index, mean ± SD Barthel Index, mean ± SD SBP (mmHg), mean ± SD Heart rate (bpm), mean ± SD Haemoglobin (g/dl), mean ± SD Creatinine (mg/dl), mean ± SD MDRD < 60 ml/min (%) Sodium (meq/l), mean ± SD Potassium (meq/l), mean ± SD Urate (mg/dl), mean ± SD NT-proBNP (pg/ml), mean ± SD Positive troponin I (%)

235 (6.6%) 230 (6.5%) 824 (23%) 370 (10.4%) 1103 (31%) 1251 (35%) 1974 (56%) 3065 (86%) 870 (25%) 1936 (55%) 3.1 (2.5) 83.1 (21.6) 138.5 (27.3) 87.6 (23.1) 12.1 (2.4) 1.4 (3.6) 58.4 (26.2) 138.7 (5.4) 4.4 (3.3) 7.9 (2.8) 6382 (8348) 184 (16%)

87 (7.9%) 68 (6.2%) 348 (31%) 84 (7.6%) 292 (26%) 362 (33%) 541 (49%) 910 (82%) 217 (20%) 574 (52%) 2.4 (2.2) 87.3 (19.7) 142.1 (27.4) 92.9 (24.9) 12.5 (2.1) 1.2 (0.6) 64.2 (26.6) 139 (4.7) 4.4 (4.3) 7.8 (3.3) 5678 (9456) 66 (17%)

148 (6.1%) 162 (6.6%) 476 (19%) 286 (12%) 811 (33%) 889 (36%) 1433 (59%) 2155 (88%) 653 (27%) 1362 (56%) 3.4 (2.6) 81.2 (22.2) 136.9 (27.1) 85.3 (21.8) 11.9 (2.5) 1.5 (4.4) 55.8 (25.6) 138.6 (5.6) 4.4 (2.7) 8 (2.6) 6706 (7768) 118 (16%)

0.049 0.659 <0.001 <0.001 <0.001 0.040 <0.001 <0.001 <0.001 0.038 <0.001 <0.001 <0.001 <0.001 <0.001 0.045 <0.001 0.025 0.848 0.132 0.019 0.735

Chest X-ray (%) Cardiomegaly Acute lung oedema Pleural effusion NYHA I–II (%) NYHA III–IV (%) LVEF < 40 (%) LVEF 40–49 (%) LVEF ≥ 50 (%)

3115 (89%) 310 (8.9%) 1613 (46%) 2213 (63%) 1317 (37%) 823 (23%) 530 (15%) 2196 (62%)

951 (87%) 75 (6.8%) 508 (46%) 823 (75%) 279 (25%) 229 (21%) 156 (14%) 720 (65%)

2164 (90%) 235 (9.8%) 1105 (46%) 1390 (57%) 1038 (43%) 594 (24%) 374 (15%) 1476 (60%)

0.003 0.005 0.884 <0.001 <0.001 0.020 0.387 0.007

Treatment at discharge (%) ACEI/ARA II Beta blockers Antialdosterone DOAC Dicoumarins Antiplatelet drugs Estatins Digoxin

2504 (71%) 2116 (60%) 1068 (30%) 135 (3.8%) 1650 (46%) 1268 (36%) 1607 (45%) 742 (21%)

811 (73%) 637 (58%) 250 (23%) 35 (3.2%) 478 (43%) 378 (34%) 459 (42%) 195 (18%)

1693 (69%) 1479 (60%) 818 (33%) 100 (4.1%) 1172 (48%) 890 (36%) 1148 (47%) 547 (22%)

0.012 0.112 <0.001 0.218 0.010 0.212 0.003 0.001

0.011 0.293 0.480

DOAC: direct oral anticoagulants; ARA II: angiotensin II receptor antagonist; COPD: chronic obstructive pulmonary disease; LVEF: left ventricular ejection fraction; HF: heart failure; AHF: acute heart failure; ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; MDRD: modification of diet in renal disease; NT-proBNP: N-terminal brain natriuretic propeptide; NYHA New York Heart Association; SBP: systolic blood pressure; ACS: acute coronary syndrome. Table 2 Analysis of events in patients with de novo acute heart failure versus decompensated chronic HF. Total (n = 3550)

De novo (n = 1105)

Decompensated chronic (n = 2445)

p-value

Mortality from all causes (%) At three months At 12 months

331 (9.3%) 818 (23%)

63 (5.7%) 168 (15%)

268 (11%) 650 (27%)

<0.01 <0.01

Cardiovascular mortality (%) At three months At 12 months

168 (4.7%) 354 (10%)

29 (2.6%) 55 (5%)

139 (5.7%) 299 (12%)

<0.01 <0.01

712 (20%) 1465 (41%)

161 (15%) 363 (33%)

551 (23%) 1102 (45%)

<0.01 <0.01

74 (6.7%) 173 (16%) 9.4 (3.2)

335 (14%) 671 (27%) 11 (6)

<0.01 <0.01 <0.01

Hospital re-admission for all causes (%) At three months At 12 months

Hospital re-admission for cardiovascular causes (%) 409 (11.5%) At three months 844 (24%) At 12 months 10.5 (5.7) Hospitalisation, mean days ± SD

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C 1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

Cumulative survival

A 1.0

0.0

Group De novo Chronic De novo-censored Chronic-censored

0.0 0

2

4

6

8

10

12

months

B 1.0

D 1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

Cumulative survival

131

0.0

0

2

4

0

2

4

6

8

10

12

6

8

10

12

months

0.0 0

2

4

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8

10

12

months

months

Fig. 1. Kaplan–Meier curves of mortality and readmissions for all cardiovascular causes, according to acute de novo versus decompensated chronic heart failure. (A) Total mortality per year, log-rank ratio, p-value <0.001. (B) Re-admissions for any cause per year, log-rank ratio, p-value <0.001. (C) Cardiovascular mortality per year, log-rank ratio, p-value <0.001. (D) Cardiovascular re-admission per year, log-rank ratio, p-value < 0.001.

Survival functions Group

1.0

De novo Chronic De novo-censored Chronic-censored

Cumulative survival

0.8

0.6

0.4

0.2

0.0 0

2

4

6

8

10

12

months Fig. 2. Kaplan–Meier curve for combined total mortality/readmissions at one year of follow-up, according to patients with acute de novo heart failure versus decompensated chronic HF, log-rank ratio, p-value <0.001.

published European HF registries, which show prevalences of de novo AHF at between 25 and 51%.4,5 From the most relevant findings of our study, we want to highlight the differences observed in the clinical profile of the groups studied. The patient with de novo AHF who is admitted to Internal Medicine services is younger and the aetiology of their HF is predominantly hypertensive compared to ischaemic and valvular which predominate in the other group. This could be due to a usual hospital practice in Spain, where patients with AHF and suspected ischaemic aetiology are admitted to mainly cardiology services, or conversely, upon the usually insidious and progressive presentation of valvular heart diseases with few episodes of AHF.

The baseline functional status, measured by the Barthel index, was better in the de novo group and was associated as an independent variable with better prognosis in our cohort. The overall comorbidity was lower in the de novo group, a fact probably related to the longer evolution time of patients with decompensated chronic HF, a clinical syndrome with progressive multiorgan failure that leads to the development of different degrees of renal failure, anaemia or malnutrition, among others. Worth noting is the high prevalence of atrial fibrillation in the de novo group, which was present in a little more than half of the cases; also, worth mentioning is that it is higher than that presented in another Spanish cohort of patients with HF corresponding to the services of Cardiology (39%).15 This data could be associated to the fact that patients admitted to the Internal Medicine services who are registered in the RICA are usually older, have a higher degree of comorbidity and a predominance of preserved LVEF, where atrial fibrillation is very present.16 With regard to readmission and mortality rates, these are double in the group of decompensated chronic HF compared to the de novo AHF group, both in the short and medium term, this could be explained by the fact that HF is a progressive disorder that increases its mortality as it advances with a 50% survival at five years in patients with advanced HF, even with adequate treatment. Conversely, patients with HF present, during their evolution, an increasingly frequent risk of hospital readmissions, with a progressive shortening of the time between episodes and, in turn, a greater associated risk of death. An interesting fact was the predominance of non-cardiovascular causes, both readmissions and mortality in the total population and in both groups separately, in this sense, a similar cohort observed that up to 75% of readmissions in patients with IC were due to non-cardiovascular and preventable causes.17 This high percentage of deaths from non-cardiovascular causes, also observed in other series,18,19 reflects the high comorbidity of patients with

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Table 3 Univariate and multivariate analysis of factors associated with mortality per year in patients with acute de novo heart failure. Variables

Univariate analysis

Multivariate analysis

HR (95% confidence interval)

p

Age, years Sex male BMI (kg/m2 )a Valvular aetiology ACS as a precipitant of AHF Charlson Index Barthel Index Haemoglobin MDRD < 60 ml/min Urate (mg/dl) NYHA III-IV

1.05 (1.03–1.07) 1.37 (1.01–1.86) 0.93 (0.90–0.96) 1.48 (0.98–2.24) 1.68 (1.05–2.68) 1.19 (1.13–1.26) 0.98 (0.97–0.98) 0.90 (0.84–0.97) 2.02 (1.66–2.45) 1.06 (1.03–1.09) 1.65 (1.20–2.27)

<0.001 0.043 <0.001 0.060 0.030 <0.001 <0.001 0.005 <0.001 <0.001 0.002

Treatment at discharge ACEI and/or ARA II Beta blockers Aldosterone antagonist Antiplatelet drugs Statins (%)

0.60 (0.44–0.82) 0.60 (0.45–0.82) 1.58 (1.14–2.19) 1.67 (1.23–2.27) 0.81 (0.59–0.90)

0.001 0.001 0.006 <0.001 0.005

HR (95% confidence interval)

p

0.94 (0.91–0.97)

<0.001

1.11 (1.04–1.18) 0.98 (0.97–0.99)

0.002 <0.001

1.73 (1.38–2.16)

<0.001

0.70 (0.50–0.98) 0.57 (0.41–0.79) 2.13 (1.52–2.99) 1.87 (1.33–2.63) 0.62 (0.44–0.87)

0.038 <0.001 <0.001 <0.001 0.006

ARA II: angiotensin II receptor antagonist; AHF: acute heart failure; ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; MDRD: modification of diet in renal disease; NT-proBNP: N-terminal brain natriuretic propeptide; NYHA: New York Heart Association; ACS: acute coronary syndrome. a Expressed in numerical value (kg/m2 ) to facilitate the interpretation of the HR.

AHF admitted to Internal Medicine services, who are increasingly elderly and fragile. This implies the need for a more comprehensive treatment in these patients and greater coordination between the different areas of health care, at the community level, acute hospital care and/or long-term/palliative care. In the treatment of AHF, multiple intervention studies show better survival in HFrEF when prescribing ACEI/ARA II, beta blockers and anti-aldosterone agents,20–22 while these showed very few effects on survival rates for HFpEF, and, so far, no evidence for HFiEF. In the multivariate analysis carried out for our cohort, we observed a better survival in those patients with de novo AHI in whom ACEI/ARA II, beta blockers and/or statins were prescribed at hospital discharge. These findings concur with those previously found in the SENIORS cohort, which also had a high average age similar to our series, and a high proportion of patients with atrial fibrillation, where the positive impact of beta-blockers was demonstrated in patients with HFpEF, in which their survival and readmission rate improved.23 With regard to statins, the results are controversial; however, in our RICA cohort, the presence of a significant number of patients with high degrees of comorbidity could condition the existence of various pathophysiological mechanisms of endothelial dysfunction and sustained inflammatory response, a scenario in which statins seem to improve survival.24,25 When we analysed the de novo group according to the LVEF, we found a clear predominance of preserved LVEF, followed by the reduced and finally the improved range (65%, 20% and 14%, respectively). The proportion of patients with HFpEF in our cohort was higher than that observed in a large Italian multicentre cohort of 1669 patients, in which 49% of patients with de novo AHF had HFpEF, and 51% had HFrEF.26 The analysis of the patients’ clinical profiles according to LVEF, confirmed the already known differential patterns, in this sense, HFrEF is more associated with the male sex and ischaemic heart disease, while HFpEF is more associated with older patients, females, a hypertensive aetiology, presence of atrial fibrillation and obesity. Our study, in turn, incorporated an analysis of patients with HFiEF, a group that is still quite unknown and that has relatively few published data. The results showed that patients with de novo AHF with HFiEF had shared characteristics with the other two groups (HFpEF and HFrEF), supporting the idea

that they represent a transition. However, regarding our analysis of the rates of readmissions and mortality according to LVEF, our study did not show any significant differences during the first year of follow-up, data that is consistent with those described in the REDINSCOR registry of patients hospitalised for HF in Spanish Cardiology services.13 Finally, the strengths of the study are the large cohort studied based on the RICA registry at the national level, and the fact that the patients included were sourced from the ‘real world’ and the usual clinical practice of Internal Medicine services, which translates into a group of patients with advanced age and multiple comorbidities. However, the present work also has some limitations that we should mention. Firstly, the data was taken exclusively from Internal Medicine services, complicating the extrapolation of results to the general population of patients with AHF, especially in terms of baseline characteristics and aetiology, which differ from Cardiology services cohorts. In addition, as mentioned in the methodology, patients who died during the initial admission were not included in the RICA registry and, therefore, their characteristics could not be analysed. This limitation probably had little impact in our study, since it is known that the number of patients with de novo AHF who die during first hospitalisation is usually low. Secondly, not evaluating the time elapsed from diagnosis of HF in patients with chronic HF does not allow us to discern whether this parameter could have played a greater role in the assessment of readmissions and mortality in this group. Finally, the RICA registry cohort did not have patients’ analytical data registered uniformly, such as NT-proBNP and troponins, which hindered its assessment as a prognostic marker. As conclusions we can state that de novo AHF represents a third of the admissions in the RICA registry due to AHF and that its clinical and prognosis profile is significantly better compared to patients with decompensated chronic HF. The main predictors of mortality per year in de novo AHF are global comorbidity, renal function and type of treatment given at hospital discharge. Conversely, the type of LVEF, whether preserved, reduced or improved, did not involve prognostic differences in the short and medium term.

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Table 4 Clinical characteristics and mortality of de novo heart failure, according to the left ventricular ejection fraction. Total (n = 1105)

LVEF < 40 (n = 229)

LVEF 40–49 (n = 156)

LVEF ≥ 50 (n = 720)

p

Age, years Female (%) BMI, kg/m2

78.8 (8.9) 571 (52%) 29.1 (5.4)

75.5 (10.7) 84 (37%) 28 (5.3)

79 (9.1) 57 (37%) 28.6 (5.6)

79.7 (8) 430 (60%) 29.6 (5.3)

0.001 <0.001 0.001

Aetiology of HF (%) Ischaemic Hypertensive Valvular Others Diabetes mellitus (%) Arterial hypertension (%) COPD (%) Atrial fibrillation (%) Charlson Index Barthel Index SBP mmHg Heart rate, bpm Haemoglobin g/dl Creatinine mg/dl MDRD < 60 ml/min (%) Sodium (meq/l), mean ± SD Potassium (meq/l), mean ± SD NT-proBNP (pg/ml), mean ± SD Troponin I (%) positive

265 (24%) 465 (42%) 132 (12.0%) 240 (22%) 541 (49%) 910 (82%) 217 (20%) 574 (52%) 2.4 (2.2) 87.3 (19.7) 142.1 (27.4) 92.9 (24.9) 12.5 (2.1) 1.2 (0.6) 64.2 (26.6) 139 (4.7) 4.4 (4.3) 5678 (9456) 66 (17%)

94 (41%) 38 (17%) 14 (6.2%) 81 (36%) 97 (42%) 168 (73%) 44 (19%) 89 (39%) 2.5 (2.5) 89.4 (19.2) 137.1 (26.3) 96.8 (25.2) 13 (2.2) 1.2 (0.5) 64.8 (26.5) 138.5 (5) 4.3 (0.6) 9027 (15 029) 21 (22%)

66 (42%) 39 (25%) 22 (14%) 29 (19%) 75 (48%) 120 (77%) 28 (18%) 83 (53%) 2.4 (2) 88.2 (19.5) 146.6 (28) 96.4 (25.3) 12.7 (2.1) 1.2 (0.5) 65.6 (26.9) 139.6 (3.9) 4.2 (0.5) 6169 (9232) 12 (20%)

105 (15%) 388 (54%) 96 (13%) 130 (18%) 369 (51%) 622 (86%) 145 (20%) 402 (56%) 2.3 (2.1) 86.5 (19.8) 142.7 (27.4) 90.8 (24.6) 12.3 (2) 1.2 (0.6) 63.7 (26.6) 139.1 (4.7) 4.5 (5.2) 4543 (6719) 33 (14%)

<0.001 <0.001 0.010 <0.001 0.062 <0.001 0.810 <0.001 0.363 0.131 0.002 0.001 0.001 0.475 0.656 0.063 0.747 0.001 0.148

Electrocardiogram No conduction alteration Block right branch Block left branch NHYA I–II (%) NYHA III–IV (%)

804 (73%) 119 (10.8%) 181 (16%) 823 (75%) 279 (25%)

141 (62%) 15 (6.6%) 73 (32%) 156 (68%) 73 (32%)

109 (70%) 16 (10%) 31 (20%) 119 (76%) 37 (24%)

554 (77%) 88 (12%) 77 (11%) 548 (76%) 169 (24%)

<0.001 0.052 <0.001 0.037 0.037

Total mortality Three months 12 months

63 (5.7%) 168 (15%)

14 (6.1%) 42 (18%)

8 (5.1%) 25 (16%)

41 (5.7%) 101 (14%)

0.920 0.272

Cardiovascular mortality Three months 12 months Re-admission at three months Re-admission at 12 months

29 (2.6%) 55 (5%) 161 (15%) 363 (33%)

9 (3.9%) 17 (7.4%) 30 (13%) 69 (30%)

4 (2.6%) 8 (5.1%) 20 (13%) 47 (30%)

16 (2.2%) 30 (4.2%) 111 (15%) 247 (34%)

0.371 0.142 0.550 0.371

Treatment at discharge (%) ACEI and/or ARA II Beta blockers Aldosterone antagonist DOAC Dicoumarins Antiplatelet drugs Estatins Digoxin

811 (73%) 637 (58%) 250 (23%) 35 (3.2%) 478 (43%) 378 (34%) 459 (42%) 195 (18%)

172 (75%) 173 (76%) 94 (41%) 4 (1.7%) 82 (36%) 98 (43%) 103 (45%) 33 (14%)

119 (76%) 103 (66%) 41 (26%) 6 (3.8%) 63 (40%) 65 (42%) 68 (44%) 25 (16%)

520 (72%) 361 (50%) 115 (16%) 25 (3.5%) 333 (46%) 215 (30%) 288 (40%) 137 (19%)

0.468 <0.001 <0.001 0.375 0.016 <0.001 0.352 0.237

DOAC: direct oral anticoagulants; ARA-II: angiotensin II receptor antagonist; COPD: chronic obstructive pulmonary disease; HF: heart failure; ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; MDRD: modification of diet in renal disease; NT-proBNP: N-terminal brain natriuretic propeptide; NYHA: New York HeartAssociation; SBP: systolic blood pressure.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements We would like to thank all the researchers who are part of the RICA Registry. This project was possible thanks to Boehringer Ingelheim’s no restrictions educational grant. We would also like to thank the RICA S & H Medical Science Service Records Coordination Centre for its quality control data, logistical support and administrative work, and Professor Salvador Ortiz, from the Autonomous University of Madrid and Statistical Advisor for S & H Medical Science Service for the data presented in this work.

Appendix A. Members of the RICA registry L. Anarte, O. Aramburu, J.C. Arévalo-Lorido, S. Carrascosa, M. Carrera, J.M. Cepeda, J.M. Cerqueiro, A. Conde-Martel, M.F. Dávila, J. Díez-Manglano, F. Epelde, F. Formiga, J. Franco, D. García-Escrivá, A. González Franco, P. Llàcer, G. López-Castellanos, L. Manzano, M. Montero-Pérez-Barquero, A. Muela, J. Pérez-Silvestre, M.A. Quesada, B. Roca, R. Ruíz-Ortega, J.A. Satué, L. Soler-Rangel, J.C. Trullàs.

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