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Incremental Prognostic Value of Conventional Echocardiography in Patients with Acutely Decompensated Heart Failure

Abstract

Background:

Acutely decompensated heart failure (ADHF) presents high morbidity and mortality in spite of therapeutic advance. Identifying factors of worst prognosis is important to improve assistance during the hospital phase and follow-up after discharge. The use of echocardiography for diagnosis and therapeutic guidance has been of great utility in clinical practice. However, it is not clear if it could also be useful for risk determination and classification in patients with ADHF and if it is capable of adding prognostic value to a clinical score (OPTIMIZE-HF).

Objective:

To identify the echocardiographic variables with independent prognostic value and to test their incremental value to a clinical score.

Methods:

Prospective cohort of patients consecutively admitted between January 2013 and January 2015, with diagnosis of acutely decompensated heart failure, followed up to 60 days after discharge. Inclusion criteria were raised plasma level of NT-proBNP (> 450 pg/ml for patients under 50 years of age or NT-proBNP > 900 pg/ml for patients over 50 years of age) and at least one of the signs and symptoms: dyspnea at rest, low cardiac output or signs of right-sided HF. The primary outcome was the composite of death and readmission for decompensated heart failure within 60 days.

Results:

Study participants included 110 individuals with average age of 68 ± 16 years, 55% male. The most frequent causes of decompensation (51%) were transgression of the diet and irregular use of medication. Reduced ejection fraction (<40%) was present in 47% of cases, and the NT-proBNP median was 3947 (IIQ = 2370 to 7000). In multivariate analysis, out of the 16 echocardiographic variables studied, only pulmonary artery systolic pressure remained as an independent predictor, but it did not significantly increment the C-statistic of the OPTMIZE-HF score.

Conclusion:

The addition of echocardiographic variables to the OPTIMIZE-HF score, with the exception of left ventricular ejection fraction, did not improve its prognostic accuracy concerning cardiovascular events (death or readmission) within 60 days

Keywords:
Heart Failure; Indicators of Morbidity and Mortality; Prognosis; Echocardiography / methods; Hypergravity; Reference Drugs

Resumo

Fundamento:

A insuficiência cardíaca agudamente descompensada (ICAD) apresenta elevada morbimortalidade a despeito do avanço terapêutico. Identificar fatores de pior prognóstico é importante para melhorar a assistência durante a fase hospitalar e acompanhamento após a alta. A utilização da ecocardiografia para diagnóstico e guia terapêutico tem sido de grande utilidade na prática clínica, contudo não está claro se também pode ser útil para determinação e classificação de risco desses pacientes e se é capaz de incrementar valor prognóstico a um escore clínico (OPTIMIZE-HF).

Objetivo:

Identificar as variáveis ecocardiográficas com valor prognóstico independente e testar seu valor incremental a um escore clínico.

Métodos:

Coorte prospectiva de pacientes consecutivamente admitidos entre janeiro de 2013 a janeiro de 2015, com diagnóstico de insuficiência cardíaca agudamente descompensada, acompanhados até 60 dias após a alta hospitalar. Os critérios de inclusão foram o aumento da dosagem plasmática do NT-proBNP (> 450 pg/ml para pacientes abaixo de 50 anos ou NT-proBNP > 900 pg/ml para pacientes acima de 50 anos) e pelo menos um dos sinais e sintomas: dispnéia em repouso, baixo débito cardíaco ou sinais de IC direita. O desfecho primário foi a combinação de óbito e reinternamento por insuficiência cardíaca descompensada em até 60 dias.

Resultados:

Foram estudados 110 indivíduos com média de idade 68 ± 16 anos, 55% do sexo masculino, sendo a transgressão da dieta/uso irregular de medicações a causa mais frequente de descompensação (51%). Fração de ejeção reduzida (< 40%) estava presente em 47% os casos, e a mediana do NT-proBNP era 3947 (IIQ = 2370 a 7000). Na análise multivariada, das 16 variáveis ecocardiográficas estudadas, somente a pressão sistólica de artéria pulmonar permaneceu como preditora independente, no entanto, não incrementou significativamente a estatística-C do escore OPTIMIZE-HF.

Conclusão:

A adição de variáveis ecocardiográficas, que não a fração de ejeção do ventrículo esquerdo, ao escore OPTIMIZE-HF, não melhorou a acurácia prognóstica do mesmo no que diz respeito a eventos cardiovasculares (morte ou re-hospitalização) em até 60 dias. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0)

Palavras-chave:
Insuficiência Cardíaca; Indicadores de Morbimortalidade; Prognóstico; Ecocardiografia / métodos; Hipergravidade; Medicamentos de Referência

Introduction

Acutely decompensated heart failure (ADHF) is a complex and heterogeneous syndrome characterized by the sudden or gradual onset of the signs or symptoms of heart failure, requiring immediate medical attention and treatment.11 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):603-69. doi: 10.1093/eurjhf/hfs105.
https://doi.org/10.1093/eurjhf/hfs105...
Mortality reaches 20% within 1 year after the diagnosis, and increases with clinical severity. In those patients with NYHA functional class IV, it can reach 80% within 2 years.22 Fonarow GC. The treatment target in acute decompensated heart failure. Rev Cardiovasc Med. 2001;2(Suppl 2):S7-S12. PMID: 12439356.,33 American Heart Association.(AHA). Heart and stroke statistical update. Dallas (USA): AHA; 2002. [Accessed in 2016 Feb 20]. Available from: http://www.heart.org/HEARTORG/General/Heart-and-Stroke-Association-Statistics-UCM-19064_SubHomePage.jsp
http://www.heart.org/HEARTORG/General/He...
The first hospitalization constitutes an important step in the clinical evolution, modifying the quality of life and survival of patients with heart failure.44 Schocken DD, Benjamin EJ, Fonarow GC, Krumholz HM, Levy D, Mensah GA, et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2008;117(19):2544-65. doi: 10.1161/CIRCULATIONAHA.107.188965.
https://doi.org/10.1161/CIRCULATIONAHA.1...
In spite of the advances in therapeutics, readmission rates due to recurrence of symptoms are high. North American studies in patients over the age of 70 years reveal readmission rates of up to 25%, within 30 days, and 50% within 6 months.55 Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-28. doi: 10.1056/NEJMsa.0803563.
https://doi.org/10.1056/NEJMsa.0803563...
,66 O'Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55(9):872-8. doi:10.1016/j.jacc.2009.08.083.
https://doi.org/10.1016/j.jacc.2009.08.0...
Thus, the stratification of patients based on their risk profile for adverse events (such as mortality and HF decompensation) is a crucial task, with a view to improve therapeutic planning and identification of the higher risk subgroup which may benefit from closer monitoring and/or more advanced therapies.77 Smith WR, Poses RM, McClish DK, Huber EC, Clemo FL, Alexander D, et al. Prognostic judgments and triage decisions for patients with acute congestive heart failure. Chest. 2002;121(5):1610-7. PMID:12006451.,88 Poses RM, Smith WR, McClish DK, Huber EC, Clemo FL, Schmitt BP, et al. Physicians' survival predictions for patients with acute congestive heart failure. Arch Intern Med. 1997;157(9):1001-7. PMID: 9140271.

Several probabilistic risk models, using clinical variables, have been proposed to predict events in the short and long run.66 O'Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55(9):872-8. doi:10.1016/j.jacc.2009.08.083.
https://doi.org/10.1016/j.jacc.2009.08.0...
,99 Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, et al. Echocardiographic evaluation of hemodynamics in patients with decompensated systolic heart failure. Circ Cardiovasc Imaging. 2011;4(3):220-7. doi: 10.1161/CIRCIMAGING.111.963496.
https://doi.org/10.1161/CIRCIMAGING.111....

10 Carluccio E, Dini FL, Biagioli P, Lauciello R, Simioniuc A, Zuchi C, et al. The 'Echo Heart Failure Score': an echocardiographic risk prediction score of mortality in systolic heart failure. Eur J Heart Fail. 2013;15(8):868-76. doi: 10.1093/eurjhf/hft038.
https://doi.org/10.1093/eurjhf/hft038...

11 Giannuzzi P, Temporelli PL, Bosimini E, Silva P, Imparato A, Corra U, et al. Independent and incremental prognostic value of Doppler-derived mitral deceleration time of early filling in both symptomatic and asymptomatic patients with left ventricular dysfunction. J Am Coll Cardiol.1996;28(2):383-90. doi: 10.1016/0735-1097(96)00163-5.
https://doi.org/10.1016/0735-1097(96)001...
-1212 Grayburn PA, Appleton CP, DeMaria AN, Greenberg B, Lowes B, Oh J, et al. Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST). J Am Coll Cardiol. 2005;45(7):1064-71. doi: 10.1016/j.jacc.2004.12.069.
https://doi.org/10.1016/j.jacc.2004.12.0...
Among them is a large registry, the OPTIMIZE-HF1313 Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol. 2008;52(5):347-56. doi: 10.1016/j.jacc.2008.04.028.
https://doi.org/10.1016/j.jacc.2008.04.0...
(Organized Program to Initiate Lifesaving Treatment in Hospitalized HF Patients), which provided data on hospital mortality and rehospitalization/death within 60 days after hospitalization using clinical and laboratory variables. In this prognostic model, the only echocardiographic variable tested was left ventricular ejection fraction, computed dichotomously. Other traditional echocardiographic parameters, such as cavity dimensions, left ventricular diastolic function, right ventricular diastolic function, valvular and hemodynamic changes have not been analysed. The association between echocardiographic variables and cardiovascular outcomes, in other studies,66 O'Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55(9):872-8. doi:10.1016/j.jacc.2009.08.083.
https://doi.org/10.1016/j.jacc.2009.08.0...
,1414 Kalogeropoulos AP, Georgiopoulou VV, Gheorghiade M, Butler J. Echocardiographic evaluation of left ventricular structure and function: new modalities and potential applications in clinical trials. J Card Fail.2012;18(2):159-72. doi: 10.1016/j.cardfail.2011.10.019.
https://doi.org/10.1016/j.cardfail.2011....
,1515 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-847. doi: 10.1093/eurheartj/ehs104.
https://doi.org/10.1093/eurheartj/ehs104...
generates the hypothesis that they may add value to the traditional prognostic models.

As a result, we conducted a study which tests the hypothesis that multiple echocardiographic variables increment the prognostic accuracy of traditional risk prediction by using the OPTIMIZE-HF score.

Methods

Population selection

Individuals consecutively hospitalized for ADHF were selected in the cardiac unit of a tertiary hospital, from January 2013 to January 2015. The inclusion criteria for this Registry included individuals with 18 years of age or more and elevated plasma levels of NT-proBNP (> 450 pg/ml in patients < 50 years of age, or > 900 pg/ml in those aged ≥ 50 years), whose hospitalization occurred due to: dyspnea at rest or in the last 15 days; signs of low cardiac output (hypotension - SBP < 90 mmHg; oliguria-diuresis < 0,5 ml/Kg/h; or lowered level of consciousness) or signs of right heart failure (hepatomegaly, lower limb edema or jugular stasis). Pregnant women, patients who did not present adequate acoustic window and those who did not consent to participate in the study were excluded. The protocol is in conformity with the declaration of Helsinki, it was approved by the Research Ethics Committee of the institution and all patients signed a free and clarified consent term.

Plasma NT-proBNP dosage

The dosage of NT-proBNP was performed on a blood sample collected immediately after the arrival of the patient to the emergency departament, a procedure which aims to ensure the shortest possible time between the beginning of the symptoms and the collection of material. The measurement was performed in serum using the ELFA technique (Enzyme-Linked Fluorescent Assay) and the bioMerieux VIDAS® NT-proBNP assay.

Transthoracic echocardiography and variables obtained

All the exams have been performed in the first 24 hours after admission in the hospital unit, by only one examiner, blind to clinical and laboratory information. The parameters were obtained in digital format and stored for further analysis, using the GE Vivid 7 machine and the Vivid I system with a M4S sector transducer with frequencies of 1.5 - 3.6MHz. Another trained and qualified observer reviewed the archieved images in 15% of the exams in order to test the interobserver agreement. The patients were studied in left lateral decubitus with sequential analysis of the parasternal, apical, suprasternal and subxiphoid windows. Echocardiographic parameters were assessed in conformity with the recomemndations of the American Society of Echocardiography (ASE).1616 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39.e14. doi: 10.1016/j.echo.2014.10.003.
https://doi.org/10.1016/j.echo.2014.10.0...
,1717 Rudski LG, Lai WW. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685-713. doi: 10.1016/j.echo.2010.05.010.
https://doi.org/10.1016/j.echo.2010.05.0...
The patients who did not have suboptimal acoustic window, which did not allow satisfactory analysis of the echocardiographic parameters, would not be included in the Registry.

The echocardiographic predictor variables analized were: the left ventricle diastolic diameter, left ventricle systolic diameter, right ventricle diameter, left atrial diameter, left atrial volume (indexed to body surface), tissue Doppler imaging of the tricuspid annulus (S' wave), tricuspid annular plane systolic excursion (TAPSE), left ventricular ejection fraction (Simpson's method), pulsed Doppler analysis of mitral flow (E wave, A wave, E/A relation), lateral and septal mitral annular tissue Doppler (e´septal, e´lateral, S´septal), E/e´relation, systolic pulmonary artery pressure and mitral insufficiency (moderate/severe).

OPTMIZE-HF predictive model

The OPTIMIZE-HF predictive model, assessed in all patients to admission, involves the collection of clinical and laboratory variables, such as: age, urea, sodium, heart rate, systolic blood pressure and left ventricular systolic dysfunction, in addition to antecedent history of hepatic dysfunction, depression and airway hyperactivity.1313 Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol. 2008;52(5):347-56. doi: 10.1016/j.jacc.2008.04.028.
https://doi.org/10.1016/j.jacc.2008.04.0...

Outcome variable

The primary outcome variable was defined by the composite of death (sudden death or due to HF decompensation) and readmission for ADHF within 60 days.

Data analysis

Statystical analysis

The numerical variables tested were expressed as mean and standard deviation or median and interquartile interval according to normality (Kolmogorov-Smirnov and Shapiro Wilk test), and compared between patients with or without outcome using the unpaired t-test or the Mann-Whitney test. The correlations between the dichotomous variables were performed with the chi-square test. Once outcome-associated variables were identified (p < 0.10), they were inserted into a multivariate logistic regression model, and adjusted according to the OPTIMIZE-HF score. In the final model, variables that proved to be independent predictors (p < 0.05) were added to the OPTIMIZE-HF score. The evaluation of the incremental value of echocardiographic variables was performed by comparing the C-statistic of the model, containing echocardiographic and clinical variables (ECO+OPTIMIZE-HF), with an exclusively clinical model (OPTIMIZE-HF). The areas under the ROC curve were compared using the DeLong test. To evaluate the calibration of the model, the Hosmer-Lemeshow test was performed.

SPSS Statistical Software (Version 21.0, SPSS Inc., Chicago, Illinois, USA) and MedCalc Software (Version 12.3.0.0, Mariakerke, Belgium) were used for data analysis, the latter for comparison between the ROC curves.

Sample size calculation

The sample was sized to provide a power of 80% and an alpha of 5%, for the pre-established analysis. To construct a new probabilistic model, in the logistic regression, 1 variable was included for every 5 outcomes. Sample size was calculated to detect a ROC curve with statistical significance, estimating an AUC of 0.75 and an events rate of 25%. A pilot study was carried out with 30 patients and an events rate of 36% of combined outcomes was noted. 110 patients were included, thus allowing for the inclusion of up to 8 echocardiographic variables in a logistic regression model.

Results

During the period covered by the study, 110 patients diagnosed with ADHF were included. Most patients were elderly people, with an average age of 68 ± 16 years, 55% of them male. Dyspnea was the main symptom in 92% of patients, followed by lower limb edema in 5%. The most common identifiable cause for clinical decompensation was poor drug adherence and/or diet transgression (51%), followed by infection and arrhythmia (21% and 5% respectively). The most common HF etiology was the hypertensive (47%), followed by ischemic heart failure (37%) and Chagas disease (7.2%). The median value of admission NT-proBNP was 3947 (IIQ = 2370 to 7000). The primary outcome occurred in 37 patients (34% of the sample), corresponding to 14 deaths and 23 readmissions within 60 days. The general characteristics are presented in Table 1.

Table 1
General Characteristics

Echocardiographic characteristics of the studied sample

The echocardiographic analysis has shown that most patients did not present severe left ventricular dilatation, with left ventricular diastolic diameter average of 55.5 ± 11.5 mm. On the other hand, left atrial volume index was significantly raised (47.5 ± 15.6 ml/m2).

The analysis of the systolic function has demonstrated that the average left ventricle ejection fraction was 44% ± 17%. In the subgroup of patients with reduced ejection fraction, most of them had severe systolic dysfunction, with a mean LVEF of 29.1% ± 6.5%. It was possible to determine the degree of systolic dysfunction in more than two-thirds of cases, since the other patients presented moderate/severe mitral insufficiency, atrial fibrillation and/or artificial pacemaker stimulation, which could compromise the analysis. From the total individuals evaluated with respect to left ventricular diastolic dysfunction (70 patients), grade I dysfunction (alteration in relaxation) was observed in 28.6% of cases and grades II and III dysfunction (reduced complacency) in 71.4%. However, the estimation of the left ventricular filling pressures was evaluated in all patients using the septal E/e' ratio, and a mean of 23.7±15 was obtained. Estimation of systolic pulmonary artery pressure, through analysis of tricuspid regurgitation, was calculated in all patients, and a mean of 44.4 ± 14.8mmHg was obtained. (Table 2)

Table 2
General Chatacteristics

Echocardiographic predictors

The exploratory analysis of 16 variables, which reflected morphological, functional and hemodynamic changes, was performed, as shown in Table 3. Out of those, only 3 were associated with the primary outcome: left atrial diameter, the indexed volume of the left atrium and the pulmonary artery systolic pressure. The left atrial diameter (44.5 ± 12 mm versus 41.8 ± 6 p = 0.05) and the indexed volume of the left atrium (52 ± 17 mm versus 45.5 ± 13 mm; p = 0.039) were significantly higher in the events group. With regard to the ejection fraction, there was no statistically significant difference between the groups (44.6 ± 18% versus 43.3 ± 17%; p = 0.72), however when it was examined as a dichotomous, rather than a continuous variable, there was higher prevalence of LVEF < 40% in the outcome group and with statistical significance (61% versus 52% p = 0.04). The estimation of left ventricular filling, evaluated through the analysis of the E/e´ relation, did not differ between the two groups (24 ± 13.9 versus 23.5 ± 16.7; p = 0.9). However, pulmonary artery systolic pressure was higher in the events group (49.8 ± 14.5 versus 42.6 ± 14.7; p = 0.02). The degree of the diastolic dysfunction did not differ significantly between the groups; neither did the presence of moderate/severe mitral insufficiency.

Table 3
General characteristics

Clinical and laboratory prognostic predictors

Comparing the non-events group with the events group (death or readmission), no statiscally significant difference was seen in relation to age, sex and systolic blood pressure at admission, as shown in Table 4. In the events group, it was observed that the mean heart rate was significantly higher (99 ± 14 versus 89 ± 25; p = 0.04). Lower creatinine level on admission was also noted (1.1 ± 0.5 versus 1.4 ±1.3; p = 0.08), but with no statistically significant difference. The OPTIMIZE-HF score was higher in the events group (34.3 ± 7.1 versus 29.8 ± 7.2; p = 0.003).

Table 4
OPTIMIZE-HF component variables

Independent and incremental value of echocardiographic variables

In the exploratory analysis, the left atrial volume index and the systolic pulmonary artery pressure (sPAP) were predictors of the primary outcome, and thus selected for multivariate analysis. In the logistic regression, using the OPTIMIZE-HF score and echocardiographic predictor variables, it was observed that the left atrial volume index lost statistical significance, and only the sPAP (p = 0.01) and the OPTIMIZE score (p = 0.002) remained in the final model, as shown in Table 5.

Table 5
Univariate analysis: Comparison of clinical-laboratory variables between the events and non-events groups

The accuracy of the sPAP echocardiographic variable was evaluated using the area under the ROC curve (C-statistic), which resulted in 0.66 (HR 95%; 0.55-0.77), while the area under the curve of the clinical model (OPTIMIZE-HF score) was 0.69 (HR 95%; 0.58-0.81). After sPAP was included in the model, it was observed an increase in the area under the ROC curve to 0.75 (IC 95%; 0.57-0.79). However, this increase was not significant (p = 0.17), which suggests that the echocardiographic variables used did not improve the prediction of events compared to the clinical model, as shown in Figure 1.

Figure 1
Comparison between ROC curves and C-statistics between the OPTIMIZE-HF conventional and combined (OPTIMIZE-HF+PSAP) probabilistic models, using the DeLong test

Discussion

The results of this study indicate that routinely measurable echocardiographic parameters, during a standard transthoracic echocardiography, do not seem to improve the risk stratification in patients with ADHF when associated with a clinical score that already uses left ventricular ejection fraction. Only the measurement of pulmonary artery systolic pressure was an independent predictor of death or readmission within 60 days in patients with acutely decompensated HF, but it did not add incremental value to the OPTIMIZE-HF clinical score.

There are several validated prognostic models, each of which combining different variables, which suggests how difficult it is to estimate risks in patients with ADHF. The efforts towards developing and improving such probabilistic models are justified because risk of in-hospital mortality, mortality after discharge and readmission are still elevated in spite of the evolution of specific treatment. The OPTIMIZE-HF score1313 Abraham WT, Fonarow GC, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). J Am Coll Cardiol. 2008;52(5):347-56. doi: 10.1016/j.jacc.2008.04.028.
https://doi.org/10.1016/j.jacc.2008.04.0...
is one of the tools recommended by the Brazilian Guidelines on Acute Heart Failure,1818 Montera MW, Almeida RA, Tinoco EM, Rocha RM, Moura LZ, Réa-Neto A, et al. Sociedade Brasileira de Cardiologia. [II Brazilian Guidelines on Acute Cardiac Insufficiency]. Arq Bras Cardiol.2009;93(3 Suppl 3):1-65. doi: http://dx.doi.org/10.1590/S0066-782X2009001900001.
http://dx.doi.org/10.1590/S0066-782X2009...
as well as by other international guidelines1919 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: a Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128(16):e240-327. doi: 10.1161/CIR.0b013e31829e8776.
https://doi.org/10.1161/CIR.0b013e31829e...
for risk stratification in patients with ADHF. It was developed to evaluate the risk of cardiovascular outcomes in hospital and after discharge (death and readmission). In our sample, the referred score presented regular performance with an area under the curve (AUC) of 0.69 (HR 95%; 0.58 - 0.81; p = 0.002). However, this performance was not significantly improved when echocardiographic variables were added to the score (independent predictor of outcomes), and an AUC of 0.75 (HR 95%; 0.57 - 0.79; p = 0.005) was obtained. This suggests that not all information provided by a negative echocardiogram, or that apparently could indicate a worsen evolution, may improve risk prediction, when evaluated within the context of a clinical score.

The hypothesis according to which echocardiography could have prognostic impact in patients with acutely decompensated heart failure took shape in the late 1990’s, based on a study by Sennim et al.2020 Senni M, Rodeheffer RJ, Tribouilloy CM, Evans JM, Jacobsen SJ, Bailey KR, et al. Use of echocardiography in the management of congestive heart failure in the community. J Am Coll Cardiol. 1999;33(1):164-70. PMID: 9935024. For the first time, in a population-based study, it was demonstrated that patients with HF who received echocardiographic evaluation had improved survival and were more willing to be treated with angiotensin converting enzyme inhibitors (ACE inhibitors) compared to those patients who were not evaluated by echocardiography. Since then, innumerable echocardiographic variables have been studied and identified as predictors of morbidity and mortality in acute heart failure.2121 Grayburn PA, Appleton CP, DeMaria AN, Greenberg B, Lowes B, Oh J, et al. BEST Trial Echocardiographic Substudy Investigators. Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST). J Am Coll Cardiol. 2005;45(7):1064-71. doi: 10.1016/j.jacc.2004.12.069.
https://doi.org/10.1016/j.jacc.2004.12.0...

22 Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang YT, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002;40(5):970-5. PMID: 12225725.

23 Quinones MA, Greenberg BH, Kopelen HA, Koilpillai C, Limacher MC, Shindler DM, et al. Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricula hypertrophy. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 2000;35(5):1237-44. PMID: 10758966

24 Rossi A, Cicoira M, Bonapace S, Golia G, Zanolla L, Franceschini L, et al. Left atrial volume provides independent and incremental information compared with exercise tolerance parameters in patients with heart failure and left ventricular systolic dysfunction. Heart. 2007;93(11):1420-5. doi: 10.1136/hrt.2006.101261.
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25 Pinamonti B, Di Lenarda A, Sinagra G, Camerini F. Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group. J Am Coll Cardiol. 1993;22(3):808-15. PMID: 8354816.

26 Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, et al. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol. 2000;85(7):837-42. PMID: 10758923.

27 Dokainish H, Zoghbi WA, Lakkis NM, Ambriz E, Patel R, Quinones MA, et al. Incremental predictive power of B-type natriuretic peptide and tissue Doppler echocardiography in the prognosis of patients with congestive heart failure. J Am Coll Cardiol. 2005;45(8):1223-6. doi: 10.1016/j.jacc.2005.01.025.
https://doi.org/10.1016/j.jacc.2005.01.0...
-2828 Wang M, Yip G, Yu C-M, Zhang Q, Zhang Y, Tse D, et al. Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol. 2005;45(2):272-7. doi: 10.1016/j.jacc.2004.09.059.
https://doi.org/10.1016/j.jacc.2004.09.0...
Left ventricular ejection fraction is probably the most researched variable and it has been shown to be a predictor of short2929 Adamopoulos C, Zannad F, Fay R, Mebazaa A, Cohen-Solal A, Guize L, et al. Ejection fraction and blood pressure are important and interactive predictors of 4-week mortality in severe acute heart failure. Eur J Heart Fail .2007;9(9):935-41. doi: 10.1016/j.ejheart.200706.001.
https://doi.org/10.1016/j.ejheart.200706...
and long3030 Hirata K, Hyodo E, Hozumi T, Kita R, Hirose M, Sakanoue Y, et al. Usefulness of a combination of systolic function by left ventricular ejection fraction and diastolic function by E/E' to predict prognosis in patients with heart failure. Am J Cardiol 2009;103(9):1275-9. doi: 10.1016/j.amjcard.2009.01.024.
https://doi.org/10.1016/j.amjcard.2009.0...
,3131 Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, et al. Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol. 2003;41(5):820-6. PMID: 12628728. term mortality in patients with ADHF. In our study, we observed that in those patients who had LVEF < 40%, there were more outcomes when compared to those with LVEF > 40%. However, when we compared the absolute value of LVEF, it did not predict events, which suggests that qualifying the systolic function (LV systolic dysfunction, present or absent) is more important for risk stratification than the numerical value of ejection fraction. Hemodynamic analysis of left ventricular compliance and filling pressures have also been largely studied, based on non-invasive hemodynamic analysis using conventional echocardiography.3232 Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail. 2010;12(8):826-32. doi: 10.1093/euryhf/hfg091.
https://doi.org/10.1093/euryhf/hfg091...
The assessment of mitral flow and tissue Doppler allows to infer the therapeutic response in patients with ADHF, since these ratings are directly related to ventricular preload and afterload, which vary considerably in the acute phase of decompensation.3333 Porter TR, Shillcutt SK, Adams MS, Desjardins G, Glas KE, Olson JJ, et al. Guidelines for the use of echocardiography as a monitor for therapeutic intervention in adults: a report from the American Society of Echocardiography. J Am Soc Echocardiogr. 2015;28(1):40-56. Doi: 10.1016/j.echo.2014.09.009.
https://doi.org/10.1016/j.echo.2014.09.0...
However, available data on the E/e’ relation and its prognostic meaning in the ADHF scenario are few and often conflicting. Some studies assert that this variable is not capable of providing prognostic information on these patients, when admission is evaluated in the emergency unit,3434 Arques S, Roux E, Ambrosi P, Sbragia P, Gelisse R, Pieri B, et al. Accuracy of bedside tissue Doppler echocardiography for the prediction of in-hospital mortality in elderly patients with acute heart failure with preserved left ventricular systolic function. comparison with B-type natriuretic peptide measurement. Int J Cardiol. 2007;123(1):69-72. doi: 10.1016/j.ijcard.2006.11.094.
https://doi.org/10.1016/j.ijcard.2006.11...
and others suggest that, when it is associated with LVEF, it is possible to identify those patients with higher risk of death and readmission.3030 Hirata K, Hyodo E, Hozumi T, Kita R, Hirose M, Sakanoue Y, et al. Usefulness of a combination of systolic function by left ventricular ejection fraction and diastolic function by E/E' to predict prognosis in patients with heart failure. Am J Cardiol 2009;103(9):1275-9. doi: 10.1016/j.amjcard.2009.01.024.
https://doi.org/10.1016/j.amjcard.2009.0...
In this study, the degree of diastolic dysfunction at admission, in both E/A and E/e´ relations (medial and lateral), were not capable of identifying those patients who had more or less events. Other important component of the echocardiographic analysis of patients with ADHF is the estimation of pulmonary artery systolic pressure. Most of these patients suffer from passive or mixed pulmonary hypertension, that is, a combination of passively elevated pressures and pulmonary vasoreactivity response. These types may improve acutely with blood volume normalization.3535 Georgiopoulou VV, Kalogeropoulos AP, Borlaug BA, Gheorghiade M, Butler J. Left ventricular dysfunction with pulmonary hypertension: Part 1: epidemiology,pathophysiology, and definitions. Circ Heart Fail. 2013;6(2):344-54. doi: 10.1161/CIRCHEARTFAILURE.112.000095.
https://doi.org/10.1161/CIRCHEARTFAILURE...
Several studies have shown the sPAP as an independent predictor of cardiovascular outcomes.3232 Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac structure and function, and long-term mortality in patients with acutely decompensated heart failure. Eur J Heart Fail. 2010;12(8):826-32. doi: 10.1093/euryhf/hfg091.
https://doi.org/10.1093/euryhf/hfg091...
,3636 Aronson D, Darawsha W, Atamna A, Kaplan M, Makhoul BF, Mutlak D, et al. Pulmonary hypertension, right ventricular function, and clinical outcome in acute decompensated heart failure. J Card Fail. 2013;19(10):665-71. doi: 10.1016/j.card.fail.2013.08.007.
https://doi.org/10.1016/j.card.fail.2013...
,3737 Merlos P, Núñez J, Sanchis J, Minana G, Palau P, Bodi V, et al. Echocardiographic estimation of pulmonary arterial systolic pressure in acute heart failure: prognostic implications. Eur J Intern Med. 2013;24(6):562-7. doi: 10.1016/j.ejim.2013.04.009.
https://doi.org/10.1016/j.ejim.2013.04.0...
In this study, it was observed that sPAP remained as an independent predictor of combined outcomes, even after it was adjusted to the clinical variables that composed the clinical score.

However, the statistical significance in multivariate analysis is not a sufficient requirement to state clinical relevance of the prognostic evaluation. The incremental value in relation to a usual predictive model must also be demonstrated and few studies have incorporated echocardiographic variables to a clinical predictive model and evaluated their performance using the C-statistic increment. Our study has demonstrated that the addition of the 16 (sixteen) echocardiographic variables tested (with the exception of left ventricular ejection fraction categorized as < 40% and > 40% which already composes the OPTIMIZE-HF score) did not improve the prognostic accuracy of the clinical score in predicting cardiovascular events within 60 days. Among the variables tested, the sPAP, with a C-statistic of 0.66 (HR 95%; 0.55 - 0.77) and with p = 0.01 in the logistic regression analysis, was the only one which predicted cardiovascular events within 60 days. However, when it was added to the OPTIMIZE-HF score, the C-statistic increment was not significant. As a result, in spite of its statistical significance in the multivariate analysis, the sPAP was not enough to assert the incremental prognostic value and clinical relevance of the prognostic evaluation in patients with acutely decompensated heart failure. In the review of the literature carried out, we did not find any scientific work that has examined the incremental value of conventional echocardiography to the OPTIMIZE-HF score. A small number of researches has incorporated echocardiographic variables into a clinical predictive model, aiming to evaluate the performance of these variables and their incremental value on the C-statistics of the score tested. Among them, we highlight the research published by Gripp et al.,3838 Gripp EA, Sousa AS, Mendes FS, Marinho TAS, Garcia MI, Feijó LA. Preditores ecocardiográficos de mortalidade hospitalar na insuficiência cardíaca descompensada: valor adicional ao escore ADHERE. Rev Bras Cardiol. 2012;25(6):479-88. which evaluated retrospectively the incremental value of the echocardiography to the ADHERE score, demonstrating that the sPAP added independent prognostic information and allowed a modest increment in the score’s C-statistic, around 0.07, in predicting in-hospital mortality. However, there were no reports that this increase presented statistical significance.

The main limitation of this study is its sample size and the fact that it was carried out in only one center, which means that our data cannot be generalized, nor considered definitive in relation to the lack of prognostic increment in the echocardiographic variables. Another point to highlight is the absence of a second control echocardiography in all the patients, so that the variables could have been compared before and after therapeutic optimization. Echocardiographic variations may occur, such as sPAP decrease in more than 10 mmHg, increase in LVEF from 5 to 10%, reduced degree of mitral insufficiency and/or tricuspid, as well as improved diastolic dysfunction and pericardial stroke. Furthermore, new technologies, such as speckle tracking and three-dimensional echocardiography, were not used, which could have improved the analysis of the biventricular systolic function as well as the cardiac chamber real volumes.

Conclusion

The addition of echocardiographic variables, except for left ventricular ejection fraction, to the OPTIMIZE-HF score, did not improve its prognostic accuracy in relation to cardiovascular events (death or readmission) within 60 days.

  • Sources of Funding
    There were no external funding sources for this study
  • Study Association
    This article is part of the thesis of master submitted by Fabio Luis de Jesus Soares, from Fundação Bahiana para Desenvolvimento de Pesquisa e Saúde Pública

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Publication Dates

  • Publication in this collection
    27 Nov 2017
  • Date of issue
    Dec 2017

History

  • Received
    03 Nov 2016
  • Reviewed
    17 Dec 2016
  • Accepted
    03 Mar 2017
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