ORIGINAL PAPER
Third heart sound in hospitalised patients with acute heart failure: insights from the ATTEND study Y. Minami,1 K. Kajimoto,2 N. Sato,3 T. Aokage,4 M. Mizuno,1 K. Asai,5 R. Munakata,4 D. Yumino,1 K. Murai,4 N. Hagiwara,1 K. Mizuno,5 H. Kasanuki,1 T. Takano5
1
Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan 2 Department of Cardiology, Sensoji Hospital, Tokyo, Japan 3 Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kawasaki, Japan 4 Intensive and Cardiac Care Unit, Nippon Medical School, Tokyo, Japan 5 Department of Internal Medicine, Nippon Medical School, Tokyo, Japan Correspondence to: Yuichiro Minami, Department of Cardiology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan Tel.: + 81 3 3353 8111 Fax: + 81 3 3356 0441 Email: [email protected]. ne.jp Disclosures The authors have no conflicts of interest to disclose.
SUMMARY
Introduction Acute heart failure (AHF) is one of the most common but ill-defined clinical entity in cardiovascular and emergency medicine and associated with a poor prognosis (1–3). In addition, this is the most common reason for hospitalisation in patients older than 65 years and will continue to increase in the future (1–3). However, assessment of prognosis in individual patients with AHF has been challenging because of the tremendous variability in the clinical course of the disease. Therefore, identification of prognostic risk factor in the setting of AHF is of high priority. On the other hand, physicians are becoming less proficient at performing physical examination in the modern era (4–9). Demonstrating that physical examination findings provide useful prognostic
820
What’s known
Background: Several previous studies have suggested that detection of a third heart sound (S3) in patients with chronic congestive heart failure is associated with adverse long-term outcomes. However, the short-term prognostic value of identifying an S3 on admission in patients with acute heart failure (AHF) is not well established. We therefore analysed the in-hospital prognostic value of detecting an S3 on admission in hospitalised patients with AHF. Methods: The Acute Decompensated Heart Failure Syndromes (ATTEND) study investigators enrolled 4107 patients hospitalised with AHF. Investigators evaluated the presence or absence of an S3 during routine physical examination. Results: On admission to hospital, 1673 patients (41%) had an S3. Patients with an S3 had a higher heart rate, higher serum level of B-type natriuretic peptide and higher creatinine levels than patients without an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein and total bilirubin between the two groups. Multivariate analysis adjusted for various markers of disease severity revealed that only the presence of an S3 was independently associated with an increase of in-hospital all cause death [adjusted odds ratio (OR), 1.69; 95% confidence interval (CI), 1.19–2.41; p = 0.003] and cardiac death (adjusted OR, 1.66; 95% CI, 1.08–2.54; p = 0.020) among the congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). Conclusions: Detecting an S3 on admission was independently associated with adverse in-hospital outcomes in patients with AHF. Our findings suggest that careful bedside assessment is clinically meaningful.
Several previous studies have suggested that detection of a third heart sound is associated with adverse long-term cardiovascular outcomes in patients who have chronic congestive heart failure.
What’s new
•
• •
Detection of a third heart sound at admission in patients with acute heart failure (AHF) may predict higher in-hospital mortality even after adjustment for other markers of disease severity. The associations of identifying a third heart sound and outcome were observed in a wide spectrum of AHF patients. Physical examination provides important prognostic information in AHF patients, and careful bedside assessment is clinically meaningful.
information for managing patients with a common illness such as AHF may thus encourage physicians and trainees to refine their examination skills. Among the numerous physical findings related to heart failure, a third heart sound (S3) is a lowpitched sound best heard over the left ventricular apex in the left lateral decubitus position, which occurs during the rapid filling phase of ventricular diastole (10–12). Several studies have suggested that detection of an S3 is associated with adverse longterm cardiovascular outcomes in patients who have chronic congestive heart failure (13,14). However, the short-term prognostic value of detecting an S3 on admission in patients with AHF is not well established. Therefore, the objective of this prospective cohort study was to analyse the in-hospital prognostic value of detecting an S3 in patients admitted to a hospital with AHF.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, August 2015, 69, 8, 820–828. doi: 10.1111/ijcp.12603
S3 in acute heart failure
Methods Study overview The Acute Decompensated Heart Failure Syndromes (ATTEND) study has been described in detail previously (15–18). It is a nationwide multicenter hospital-based prospective cohort study that is being conducted in Japan. The objectives of the ATTEND are to clarify the overall clinical picture for AHF patients, including demographical characteristics, clinical profile and outcomes. ATTEND is an observational study in which conventional information is collected within the scope of clinical practice, and there are no specific examinations or interventions. This study is being conducted based on the Helsinki Declaration. The study protocol was approved by the appropriate ethics committee at each participating centre, and written informed consent was obtained from all of the patients.
Patients ATTEND target patients who are admitted to hospital with AHF. A diagnosis of heart failure was made on the basis of modified Framingham criteria (16) and required the presence of two major criteria or one major and two minor criteria. AHF was defined as new-onset decompensated heart failure or exacerbation of chronic heart failure that met the above criteria and required hospitalisation. Patients were eligible for inclusion if an episode of AHF was the primary cause of admission. At the index hospitalisation, eligible individual patients were included and data were compiled on a per patient basis. Persons aged less than 20 years were excluded. We also excluded patients in whom chest symptoms, ischaemic changes on electrocardiography and serum cardiac markers indicated a diagnosis of acute coronary syndrome.
Study setting The ATTEND investigators prospectively registered 4842 patients with AHF throughout Japan from 1 April 2007 to 31 December 2011. At the time of admission, investigators evaluated the presence or absence of an S3, respiratory rales, jugular venous distension and peripheral oedema during routine physical examination before initial treatment for AHF (13,14). Each study patient was auscultated for an S3 by one or more treating cardiologists. Auscultation was performed in an emergency department or cardiac care ward at and around the left ventricular apex in the supine and left lateral decubitus positions. The end point of this study was all cause death, cardiac death and non-cardiac death during hospitalisation. These records were provided to the ª 2014 John Wiley & Sons Ltd Int J Clin Pract, August 2015, 69, 8, 820–828
End-point Classification Committee (composed of two experienced cardiologists), which then determined and categorised each event for use in the analysis.
Statistical analysis Of the 4842 subjects registered, 735 patients with incomplete data on physical findings were excluded, leaving 4107 patients for analysis. The patients excluded from the analysis because of incomplete data were similar to the cohort used in this analysis, and no statistically significant differences were observed between the two groups in terms of cardiac (4.8% vs. 4.5%, p = 0.689), and non-cardiac (1.9% vs. 1.9%, p = 0.890) death rate. Results are presented as mean with standard deviation, median with interquartile range or frequencies. Student’s t-test was used to compare normally distributed continuous variables between groups and the Mann–Whitney Utest was used for skewed continuous or ordinal variables. The v2 test or Fisher’s exact test was used to compare nominal variables. To evaluate the impact of an S3 on the in-hospital prognosis, univariate and multivariate logistic regression models were used. Multivariate models included the age, sex, aetiology of heart failure, history of heart failure hospitalisation, hypertension, dyslipidaemia, diabetes, smoking, ventricular arrhythmia, pacemaker use (including implantable defibrillators and cardiac resynchronisation therapy), stroke, chronic pulmonary disease, haemodialysis, initial physical findings (S3, rales, jugular venous distension and peripheral oedema) and symptoms (paroxysmal nocturnal dyspnoea and orthopnea), systolic and diastolic blood pressure, heart rate, atrial fibrillation, left ventricular ejection fraction, B-type natriuretic peptide, serum sodium, haemoglobin, C-reactive protein, total bilirubin and renal insufficiency. Furthermore, heterogeneity of third heart sound’s influence with respect to total death was also evaluated in subgroup analysis. The influence of profile, interaction and multicollinearity in the final model were examined by using regression diagnostic analysis. Two-tailed p-values of less than 0.05 were considered to indicate statistical significance. Analyses were performed with the SAS system ver. 9.1 (SAS Institute, Cary, NC) at an independent biostatistics and data centre (STATZ Institute, Inc., Tokyo, Japan).
Results Demographical and clinical characteristics Among the 4107 patients enrolled with AHF, 1673 patients (40.7%) had an S3 on admission. The baseline characteristics of the cohorts with and without
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an S3 are presented in Table 1. Patients with an S3 were younger and less likely to be women than those without an S3. In addition, patients with an S3 were more likely to have an idiopathic aetiology or a history of ventricular arrhythmia as the underlying disorder. The prevalence of paroxysmal nocturnal dyspnoea, orthopnea, rales, jugular venous distension and peripheral oedema was significantly higher in patients with an S3. Furthermore, patients with an S3 had a higher heart rate, higher serum level of Btype natriuretic peptide and higher serum creatinine level. Moreover, a preserved left ventricular ejection fraction (> 40%) and atrial fibrillation were both less common in patients with an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein, total bilirubin and medications prior to admission between the two groups.
showed that patients with an S3 had a significantly increased risk of all cause death (adjusted OR, 1.69; 95% CI, 1.19–2.41; p = 0.003) and cardiac death (OR, 1.66; 95% CI, 1.08–2.54; p = 0.020), but not non-cardiac death (OR, 1.53; 95% CI, 0.87–2.69; p = 0.136). Among the four congestive physical findings, only an S3 was identified as an independent determinant of the outcome, although several findings were determinants on univariate analysis.
Outcomes
We found that detection of an S3 on admission to hospital is an important prognostic indicator in patients with AHF. It identifies patients with an increased risk of in-hospital all cause death and cardiac death, independently of other markers of disease severity. In addition, the associations of identifying an S3 and outcome were observed in a wide spectrum of AHF patients. In the present study, an S3 was detected in 41% of patients with AHF. In the SOLVD prevention trial, only 5% of the subjects had an S3 since that trial enrolled patients with asymptomatic left ventricular dysfunction (13). On the other hand, 24% of patients with symptomatic chronic congestive heart failure had an S3 in the SOLVD treatment trial (14). Furthermore, an S3 was almost ubiquitous (96%) in a study of patients with severe advanced heart failure (19). These variations in the reported prevalence could result from differences in the severity and condition of including heart failure patients. As we expected, an S3 was more common in the present cohort of subjects with AHF than in patients with stable chronic heart failure, while being less common than in patients with advanced heart failure awaiting heart transplantation. Since our findings were obtained in a large population of patients from all regions of Japan, the results provide novel epidemiological information about an S3 in the setting of AHF. An S3 was previously reported to be an unfavourable prognostic sign in patients with heart failure; however, this association was based on studies of patients undergoing non-cardiac surgery and patients with chronic or asymptomatic congestive heart failure (13,14,20). In addition to the above, the present study suggests that detection of an S3 on physical examination is an important independent
Overall, 262 patients (6.4%) in 4107 study AHF cohort died during hospitalisation including 183 patients (4.5%) with cardiac causes. In addition, 79 patients (1.9%) died with non-cardiac causes during hospitalisation, including 17 patients (21.5%) with cerebrovascular disorders, 29 patients (36.7%) with pneumonia and respiratory failure, 14 patients (17.7%) with other infectious disease including sepsis, 4 patients (5.1%) with malignancy and 15 patients (19.0%) with others and unknown causes. The incidence of in-hospital all cause death, cardiac death and non-cardiac death is shown in Figure 1 according to the presence or absence of four major congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). On univariate analysis, patients with an S3 showed a significantly higher risk of all cause death [crude odds ratio (OR), 1.62; 95% confidence interval (CI), 1.26– 2.08; p < 0.001] and cardiac death (OR, 1.72; 95% CI, 1.28–2.32; p < 0.001) than patients without an S3, while there was no difference of death from non-cardiac causes (OR, 1.36; 95% CI, 0.87–2.12; p = 0.180). Multivariate analysis adjusted for congestive physical findings and the other markers of disease severity [age, sex, aetiology of heart failure, history of heart failure hospitalisation, hypertension, dyslipidaemia, diabetes, smoking, ventricular arrhythmia, pacemaker use (including implantable defibrillators and cardiac resynchronisation therapy), stroke, chronic pulmonary disease, haemodialysis, symptoms (paroxysmal nocturnal dyspnoea and orthopnea), systolic and diastolic blood pressure, heart rate, atrial fibrillation, left ventricular ejection fraction, B-type natriuretic peptide, blood urea nitrogen, serum creatinine, sodium, haemoglobin, C-reactive protein and total bilirubin]
Subgroup analysis To evaluate the heterogeneity of prognostic value of detecting an S3 on admission with respect to all-cause mortality rate, subgroup analysis was also performed. As shown in Figure 2, there were no statistical interactions among subgroups.
Discussion
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, August 2015, 69, 8, 820–828
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difficulty in detecting an S3 may have biased our results and may thus have led to underestimation of the true magnitude of the association of this physical finding with adverse outcomes.
ATTEND study investigators for their contributions to this study.
Conclusions
YM, KK and NS made substantial contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data and drafting of the manuscript. TA, MM, KA, RM, DY, K. Murai, NH, K. Mizuno and HK contributed to the acquisition of data, the conception and design of the study and critical revision of the manuscript. TT made substantial contributions to the conception and design of the study, analysis and interpretation of data, and drafting and critical revision of the manuscript. All authors read and approved the final manuscript.
We conclude that detection of an S3 at admission in patients with AHF may predict higher in-hospital mortality even after adjustment for other markers of disease severity. Our findings emphasise that physical examination provides important prognostic information in AHF patients, and careful bedside assessment is clinically meaningful.
Acknowledgements
Author contributions
This study was supported by the Japan Heart Foundation. We express our appreciation to all of the
References 1 Yancy CW, Jessup M, Bozkurt B 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. J Am Coll Cardiol 2013; 62: e147–239. 2 McMurray JJ, Adamopoulos S, Anker SD 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: 1787–847. 3 Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009; 53: 557–73. 4 Adolph RJ. In defense of the stethoscope. Chest 1998; 114: 1235–7. 5 Craige E. Should auscultation be rehabilitated? N Engl J Med 1988; 318: 1611–3. 6 Fletcher RH, Fletcher SW. Has medicine outgrown physical diagnosis? Ann Intern Med 1992; 117: 786–7. 7 Marcus GM, Vessey J, Jordan MV et al. Relationship between accurate auscultation of a clinically useful third heart sound and level of experience. Arch Intern Med 2006; 166: 617–22. 8 Weitz HH, Mangione S. In defense of the stethoscope and the bedside. Am J Med 2000; 108: 669–71. 9 Breidthardt T, Irfan A, Klima T et al. Pathophysiology of lower extremity edema in acute heart failure revisited. Am J Med 2012; 125(1124): e1–8. 10 van de Werf F, Boel A, Geboers J et al. Diastolic properties of the left ventricle in normal adults and in patients with third heart sounds. Circulation 1984; 69: 1070–8. 11 van de Werf F, Minten J, Carmeliet P et al. The genesis of the third and fourth heart sounds. A pressure-flow study in dogs. J Clin Invest 1984; 73: 1400–7. 12 Wynne J. The clinical meaning of the third heart sound. Am J Med 2001; 111: 157–8.
13 Drazner MH, Rame JE, Dries DL. Third heart sound and elevated jugular venous pressure as markers of the subsequent development of heart failure in patients with asymptomatic left ventricular dysfunction. Am J Med 2003; 114: 431–7. 14 Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. N Engl J Med 2001; 345: 574–81. 15 Minami Y, Kajimoto K, Sato N et al. Admission time, variability in clinical characteristics, and inhospital outcomes in acute heart failure syndromes: findings from the ATTEND registry. Int J Cardiol 2011; 153: 102–5. 16 Sato N, Kajimoto K, Asai K et al. Acute decompensated heart failure syndromes (ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, and preliminary data. Am Heart J 2010; 159(949–55): e1. 17 Kajimoto K, Sato N, Keida T et al. Association between length of stay, frequency of in-hospital death, and causes of death in Japanese patients with acute heart failure syndromes. Int J Cardiol 2013; 168: 554–6. 18 Sato N, Kajimoto K, Keida T et al. Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry). Circ J 2013; 77: 944–51. 19 Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 1989; 261: 884–8. 20 Goldman L, Caldera DL, Nussbaum SR et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297: 845–50. 21 Collins SP, Peacock WF, Lindsell CJ et al. S3 detection as a diagnostic and prognostic aid in emergency department patients with acute dyspnea. Ann Emerg Med 2009; 53: 748–57. 22 Folland ED, Kriegel BJ, Henderson WG et al. Implications of third heart sounds in patients with valvular heart disease. The Veterans Affairs Cooperative Study on Valvular Heart Disease. N Engl J Med 1992; 327: 458–62.
23 Shah PM, Yu PN. Gallop rhythm. Hemodynamic and clinical correlation. Am Heart J 1969; 78: 823–8. 24 Glower DD, Murrah RL, Olsen CO et al. Mechanical correlates of the third heart sound. J Am Coll Cardiol 1992; 19: 450–7. 25 Kono T, Rosman H, Alam M et al. Hemodynamic correlates of the third heart sound during the evolution of chronic heart failure. J Am Coll Cardiol 1993; 21: 419–23. 26 Campana C, Gavazzi A, Berzuini C et al. Predictors of prognosis in patients awaiting heart transplantation. J Heart Lung Transplant 1993; 12: 756–65. 27 Binanay C, Califf RM, Hasselblad V et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005; 294: 1625–33. 28 Zile MR, Bennett TD, St John Sutton M et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008; 118: 1433–41. 29 Leri A, Claudio PP, Li Q et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local reninangiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest 1998; 101: 1326–42. 30 Azevedo ER, Newton GE, Floras JS, Parker JD. Reducing cardiac filling pressure lowers norepinephrine spillover in patients with chronic heart failure. Circulation 2000; 101: 2053–9. 31 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: 808–15. 32 Pozzoli M, Febo O, Tramarin R et al. Pulsed Doppler evaluation of left ventricular filling in subjects with pathologic and physiologic third heart sound. Eur Heart J 1990; 11: 500–8.
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Univariate analysis
No. of
End-points
events (%)
Multivariate analysis P value
Crude odds ratio (95% confidence interval)
P value
Adjusted odds ratio (95% confidence interval)
All cause death Third heart sound Rales Jugular venous distension Peripheral edema
Absent
126
(5.2%)
1.00
Present
136
(8.1%)
1.62
Absent
56
(4.7%)
1.00
Present
206
(7.0%)
1.52
Absent
87
Present
175
(7.5%)
1.52
Absent
76
(5.8%)
(4.9%)
1.00
Present
186
(6.6%)
1.15
(
1.26
-
2.08
)
Third heart sound in hospitalised patients with acute heart failure: insights from the ATTEND study Y. Minami,1 K. Kajimoto,2 N. Sato,3 T. Aokage,4 M. Mizuno,1 K. Asai,5 R. Munakata,4 D. Yumino,1 K. Murai,4 N. Hagiwara,1 K. Mizuno,5 H. Kasanuki,1 T. Takano5
1
Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan 2 Department of Cardiology, Sensoji Hospital, Tokyo, Japan 3 Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kawasaki, Japan 4 Intensive and Cardiac Care Unit, Nippon Medical School, Tokyo, Japan 5 Department of Internal Medicine, Nippon Medical School, Tokyo, Japan Correspondence to: Yuichiro Minami, Department of Cardiology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan Tel.: + 81 3 3353 8111 Fax: + 81 3 3356 0441 Email: [email protected]. ne.jp Disclosures The authors have no conflicts of interest to disclose.
SUMMARY
Introduction Acute heart failure (AHF) is one of the most common but ill-defined clinical entity in cardiovascular and emergency medicine and associated with a poor prognosis (1–3). In addition, this is the most common reason for hospitalisation in patients older than 65 years and will continue to increase in the future (1–3). However, assessment of prognosis in individual patients with AHF has been challenging because of the tremendous variability in the clinical course of the disease. Therefore, identification of prognostic risk factor in the setting of AHF is of high priority. On the other hand, physicians are becoming less proficient at performing physical examination in the modern era (4–9). Demonstrating that physical examination findings provide useful prognostic
820
What’s known
Background: Several previous studies have suggested that detection of a third heart sound (S3) in patients with chronic congestive heart failure is associated with adverse long-term outcomes. However, the short-term prognostic value of identifying an S3 on admission in patients with acute heart failure (AHF) is not well established. We therefore analysed the in-hospital prognostic value of detecting an S3 on admission in hospitalised patients with AHF. Methods: The Acute Decompensated Heart Failure Syndromes (ATTEND) study investigators enrolled 4107 patients hospitalised with AHF. Investigators evaluated the presence or absence of an S3 during routine physical examination. Results: On admission to hospital, 1673 patients (41%) had an S3. Patients with an S3 had a higher heart rate, higher serum level of B-type natriuretic peptide and higher creatinine levels than patients without an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein and total bilirubin between the two groups. Multivariate analysis adjusted for various markers of disease severity revealed that only the presence of an S3 was independently associated with an increase of in-hospital all cause death [adjusted odds ratio (OR), 1.69; 95% confidence interval (CI), 1.19–2.41; p = 0.003] and cardiac death (adjusted OR, 1.66; 95% CI, 1.08–2.54; p = 0.020) among the congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). Conclusions: Detecting an S3 on admission was independently associated with adverse in-hospital outcomes in patients with AHF. Our findings suggest that careful bedside assessment is clinically meaningful.
Several previous studies have suggested that detection of a third heart sound is associated with adverse long-term cardiovascular outcomes in patients who have chronic congestive heart failure.
What’s new
•
• •
Detection of a third heart sound at admission in patients with acute heart failure (AHF) may predict higher in-hospital mortality even after adjustment for other markers of disease severity. The associations of identifying a third heart sound and outcome were observed in a wide spectrum of AHF patients. Physical examination provides important prognostic information in AHF patients, and careful bedside assessment is clinically meaningful.
information for managing patients with a common illness such as AHF may thus encourage physicians and trainees to refine their examination skills. Among the numerous physical findings related to heart failure, a third heart sound (S3) is a lowpitched sound best heard over the left ventricular apex in the left lateral decubitus position, which occurs during the rapid filling phase of ventricular diastole (10–12). Several studies have suggested that detection of an S3 is associated with adverse longterm cardiovascular outcomes in patients who have chronic congestive heart failure (13,14). However, the short-term prognostic value of detecting an S3 on admission in patients with AHF is not well established. Therefore, the objective of this prospective cohort study was to analyse the in-hospital prognostic value of detecting an S3 in patients admitted to a hospital with AHF.
ª 2014 John Wiley & Sons Ltd Int J Clin Pract, August 2015, 69, 8, 820–828. doi: 10.1111/ijcp.12603
S3 in acute heart failure
Methods Study overview The Acute Decompensated Heart Failure Syndromes (ATTEND) study has been described in detail previously (15–18). It is a nationwide multicenter hospital-based prospective cohort study that is being conducted in Japan. The objectives of the ATTEND are to clarify the overall clinical picture for AHF patients, including demographical characteristics, clinical profile and outcomes. ATTEND is an observational study in which conventional information is collected within the scope of clinical practice, and there are no specific examinations or interventions. This study is being conducted based on the Helsinki Declaration. The study protocol was approved by the appropriate ethics committee at each participating centre, and written informed consent was obtained from all of the patients.
Patients ATTEND target patients who are admitted to hospital with AHF. A diagnosis of heart failure was made on the basis of modified Framingham criteria (16) and required the presence of two major criteria or one major and two minor criteria. AHF was defined as new-onset decompensated heart failure or exacerbation of chronic heart failure that met the above criteria and required hospitalisation. Patients were eligible for inclusion if an episode of AHF was the primary cause of admission. At the index hospitalisation, eligible individual patients were included and data were compiled on a per patient basis. Persons aged less than 20 years were excluded. We also excluded patients in whom chest symptoms, ischaemic changes on electrocardiography and serum cardiac markers indicated a diagnosis of acute coronary syndrome.
Study setting The ATTEND investigators prospectively registered 4842 patients with AHF throughout Japan from 1 April 2007 to 31 December 2011. At the time of admission, investigators evaluated the presence or absence of an S3, respiratory rales, jugular venous distension and peripheral oedema during routine physical examination before initial treatment for AHF (13,14). Each study patient was auscultated for an S3 by one or more treating cardiologists. Auscultation was performed in an emergency department or cardiac care ward at and around the left ventricular apex in the supine and left lateral decubitus positions. The end point of this study was all cause death, cardiac death and non-cardiac death during hospitalisation. These records were provided to the ª 2014 John Wiley & Sons Ltd Int J Clin Pract, August 2015, 69, 8, 820–828
End-point Classification Committee (composed of two experienced cardiologists), which then determined and categorised each event for use in the analysis.
Statistical analysis Of the 4842 subjects registered, 735 patients with incomplete data on physical findings were excluded, leaving 4107 patients for analysis. The patients excluded from the analysis because of incomplete data were similar to the cohort used in this analysis, and no statistically significant differences were observed between the two groups in terms of cardiac (4.8% vs. 4.5%, p = 0.689), and non-cardiac (1.9% vs. 1.9%, p = 0.890) death rate. Results are presented as mean with standard deviation, median with interquartile range or frequencies. Student’s t-test was used to compare normally distributed continuous variables between groups and the Mann–Whitney Utest was used for skewed continuous or ordinal variables. The v2 test or Fisher’s exact test was used to compare nominal variables. To evaluate the impact of an S3 on the in-hospital prognosis, univariate and multivariate logistic regression models were used. Multivariate models included the age, sex, aetiology of heart failure, history of heart failure hospitalisation, hypertension, dyslipidaemia, diabetes, smoking, ventricular arrhythmia, pacemaker use (including implantable defibrillators and cardiac resynchronisation therapy), stroke, chronic pulmonary disease, haemodialysis, initial physical findings (S3, rales, jugular venous distension and peripheral oedema) and symptoms (paroxysmal nocturnal dyspnoea and orthopnea), systolic and diastolic blood pressure, heart rate, atrial fibrillation, left ventricular ejection fraction, B-type natriuretic peptide, serum sodium, haemoglobin, C-reactive protein, total bilirubin and renal insufficiency. Furthermore, heterogeneity of third heart sound’s influence with respect to total death was also evaluated in subgroup analysis. The influence of profile, interaction and multicollinearity in the final model were examined by using regression diagnostic analysis. Two-tailed p-values of less than 0.05 were considered to indicate statistical significance. Analyses were performed with the SAS system ver. 9.1 (SAS Institute, Cary, NC) at an independent biostatistics and data centre (STATZ Institute, Inc., Tokyo, Japan).
Results Demographical and clinical characteristics Among the 4107 patients enrolled with AHF, 1673 patients (40.7%) had an S3 on admission. The baseline characteristics of the cohorts with and without
821
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S3 in acute heart failure
an S3 are presented in Table 1. Patients with an S3 were younger and less likely to be women than those without an S3. In addition, patients with an S3 were more likely to have an idiopathic aetiology or a history of ventricular arrhythmia as the underlying disorder. The prevalence of paroxysmal nocturnal dyspnoea, orthopnea, rales, jugular venous distension and peripheral oedema was significantly higher in patients with an S3. Furthermore, patients with an S3 had a higher heart rate, higher serum level of Btype natriuretic peptide and higher serum creatinine level. Moreover, a preserved left ventricular ejection fraction (> 40%) and atrial fibrillation were both less common in patients with an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein, total bilirubin and medications prior to admission between the two groups.
showed that patients with an S3 had a significantly increased risk of all cause death (adjusted OR, 1.69; 95% CI, 1.19–2.41; p = 0.003) and cardiac death (OR, 1.66; 95% CI, 1.08–2.54; p = 0.020), but not non-cardiac death (OR, 1.53; 95% CI, 0.87–2.69; p = 0.136). Among the four congestive physical findings, only an S3 was identified as an independent determinant of the outcome, although several findings were determinants on univariate analysis.
Outcomes
We found that detection of an S3 on admission to hospital is an important prognostic indicator in patients with AHF. It identifies patients with an increased risk of in-hospital all cause death and cardiac death, independently of other markers of disease severity. In addition, the associations of identifying an S3 and outcome were observed in a wide spectrum of AHF patients. In the present study, an S3 was detected in 41% of patients with AHF. In the SOLVD prevention trial, only 5% of the subjects had an S3 since that trial enrolled patients with asymptomatic left ventricular dysfunction (13). On the other hand, 24% of patients with symptomatic chronic congestive heart failure had an S3 in the SOLVD treatment trial (14). Furthermore, an S3 was almost ubiquitous (96%) in a study of patients with severe advanced heart failure (19). These variations in the reported prevalence could result from differences in the severity and condition of including heart failure patients. As we expected, an S3 was more common in the present cohort of subjects with AHF than in patients with stable chronic heart failure, while being less common than in patients with advanced heart failure awaiting heart transplantation. Since our findings were obtained in a large population of patients from all regions of Japan, the results provide novel epidemiological information about an S3 in the setting of AHF. An S3 was previously reported to be an unfavourable prognostic sign in patients with heart failure; however, this association was based on studies of patients undergoing non-cardiac surgery and patients with chronic or asymptomatic congestive heart failure (13,14,20). In addition to the above, the present study suggests that detection of an S3 on physical examination is an important independent
Overall, 262 patients (6.4%) in 4107 study AHF cohort died during hospitalisation including 183 patients (4.5%) with cardiac causes. In addition, 79 patients (1.9%) died with non-cardiac causes during hospitalisation, including 17 patients (21.5%) with cerebrovascular disorders, 29 patients (36.7%) with pneumonia and respiratory failure, 14 patients (17.7%) with other infectious disease including sepsis, 4 patients (5.1%) with malignancy and 15 patients (19.0%) with others and unknown causes. The incidence of in-hospital all cause death, cardiac death and non-cardiac death is shown in Figure 1 according to the presence or absence of four major congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). On univariate analysis, patients with an S3 showed a significantly higher risk of all cause death [crude odds ratio (OR), 1.62; 95% confidence interval (CI), 1.26– 2.08; p < 0.001] and cardiac death (OR, 1.72; 95% CI, 1.28–2.32; p < 0.001) than patients without an S3, while there was no difference of death from non-cardiac causes (OR, 1.36; 95% CI, 0.87–2.12; p = 0.180). Multivariate analysis adjusted for congestive physical findings and the other markers of disease severity [age, sex, aetiology of heart failure, history of heart failure hospitalisation, hypertension, dyslipidaemia, diabetes, smoking, ventricular arrhythmia, pacemaker use (including implantable defibrillators and cardiac resynchronisation therapy), stroke, chronic pulmonary disease, haemodialysis, symptoms (paroxysmal nocturnal dyspnoea and orthopnea), systolic and diastolic blood pressure, heart rate, atrial fibrillation, left ventricular ejection fraction, B-type natriuretic peptide, blood urea nitrogen, serum creatinine, sodium, haemoglobin, C-reactive protein and total bilirubin]
Subgroup analysis To evaluate the heterogeneity of prognostic value of detecting an S3 on admission with respect to all-cause mortality rate, subgroup analysis was also performed. As shown in Figure 2, there were no statistical interactions among subgroups.
Discussion
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difficulty in detecting an S3 may have biased our results and may thus have led to underestimation of the true magnitude of the association of this physical finding with adverse outcomes.
ATTEND study investigators for their contributions to this study.
Conclusions
YM, KK and NS made substantial contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data and drafting of the manuscript. TA, MM, KA, RM, DY, K. Murai, NH, K. Mizuno and HK contributed to the acquisition of data, the conception and design of the study and critical revision of the manuscript. TT made substantial contributions to the conception and design of the study, analysis and interpretation of data, and drafting and critical revision of the manuscript. All authors read and approved the final manuscript.
We conclude that detection of an S3 at admission in patients with AHF may predict higher in-hospital mortality even after adjustment for other markers of disease severity. Our findings emphasise that physical examination provides important prognostic information in AHF patients, and careful bedside assessment is clinically meaningful.
Acknowledgements
Author contributions
This study was supported by the Japan Heart Foundation. We express our appreciation to all of the
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Univariate analysis
No. of
End-points
events (%)
Multivariate analysis P value
Crude odds ratio (95% confidence interval)
P value
Adjusted odds ratio (95% confidence interval)
All cause death Third heart sound Rales Jugular venous distension Peripheral edema
Absent
126
(5.2%)
1.00
Present
136
(8.1%)
1.62
Absent
56
(4.7%)
1.00
Present
206
(7.0%)
1.52
Absent
87
Present
175
(7.5%)
1.52
Absent
76
(5.8%)
(4.9%)
1.00
Present
186
(6.6%)
1.15
(
1.26
-
2.08
)
