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Association Between Prehospital Time Interval and Short-Term Outcome in Acute Heart Failure Patients
Journal of Cardiac Failure Vol. 17 No. 9 2011
Association Between Prehospital Time Interval and Short-Term Outcome in Acute Heart Failure Patients MASASHI TAKAHASHI, MD, SHUN KOHSAKA, MD, HIROAKI MIYATA, PhD, TSUTOMU YOSHIKAWA, MD, ATSUTOSHI TAKAGI, MD, KAZUMASA HARADA, MD, TAKAMICHI MIYAMOTO, MD, TETSUO SAKAI, MD, KEN NAGAO, MD, NAOKI SATO, MD, AND MORIMASA TAKAYAMA, MD, FOR TOKYO CCU NETWORK COUNCIL Tokyo, Japan
ABSTRACT Background: Acute heart failure (AHF) is one of the most frequently encountered cardiovascular conditions that can seriously affect the patient’s prognosis. However, the importance of early triage and treatment initiation in the setting of AHF has not been recognized. Methods and Results: The Tokyo Cardiac Care Unit Network Database prospectively collected information of emergency admissions to acute cardiac care facilities in 2005e2007 from 67 participating hospitals in the Tokyo metropolitan area. We analyzed records of 1,218 AHF patients transported to medical centers via emergency medical services (EMS). AHF was defined as rapid onset or change in the signs and symptoms of heart failure, resulting in the need for urgent therapy. Patients with acute coronary syndrome were excluded from this analysis. Logistic regression analysis was performed to calculate the risk-adjusted inhospital mortality. A majority of the patients were elderly (76.1 6 11.5 years old) and male (54.1%). The overall in-hospital mortality rate was 6.0%. The median time interval between symptom onset and EMS arrival (response time) was 64 minutes (interquartile range [IQR] 26e205 minutes), and that between EMS arrival and ER arrival (transportation time) was 27 minutes (IQR 9e78 minutes). The riskadjusted mortality increased with transportation time, but did not correlate with the response time. Those who took O45 minutes to arrive at the medical centers were at a higher risk for in-hospital mortality (odds ratio 2.24, 95% confidence interval 1.17e4.31; P 5 .015). Conclusions: Transportation time correlated with risk-adjusted mortality, and steps should be taken to reduce the EMS transfer time to improve the outcome in AHF patients. (J Cardiac Fail 2011;17:742e747) Key Words: Network, heart failure, ambulance.
Acute heart failure (AHF) is one of the most frequently encountered cardiovascular conditions and can seriously affect the patient’s prognosis.1e3 However, there is little additional guidance on how emergency medical services (EMS) should optimize their time before hospital arrival. In the acute settings of other cardiovascular disease, particularly ischemic conditions, reducing the time until initial medical care is important for improving the prognosis. For example,
immediate cardiopulmonary resuscitation and defibrillation for ventricular tachycardia/fibrillation contribute to improved prognosis in patients with sudden cardiac arrest.4,5 Timely coronary reperfusion by primary percutaneous coronary intervention (PCI) is the cornerstone of modern management in the case of high-risk acute coronary syndrome; both symptom-to-reperfusion and door-to-balloon times are important predictors of ST-segment elevation myocardial infarction (STEMI).6,7 Current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) recommend that the interval from the first medical contact to PCI be !90 minutes for individuals experiencing STEMI. Early and appropriate intervention to AHF patients may aid in improving the short-term outcome of AHF. The present study aimed to describe the preehospital system time intervals from symptom onset to Emergency Room (ER) arrival to assess the relationship between the time intervals
From the Tokyo CCU Network Scientific Committee, Tokyo, Japan. Manuscript received December 17, 2010; revised manuscript received April 17, 2011; revised manuscript accepted May 9, 2011. Reprint requests: Shun Kohsaka, MD, Department of Cardiology, Keio University Hospital, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] See page 746 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.05.005
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and in-hospital mortality and to derive theoretic benchmarks for system time intervals in AHF patients admitted in hospitals belonging to the Tokyo Cardiac Care Unit Network (TCN; Appendix 1).
time) and the time for transportation to the ER via ambulance (transportation time). Time until triage at the ER was not measured in this registry.
Methods
The present analysis was designed to compare the relationship between prehospital time interval and in-hospital mortality. The prehospital time interval was divided into response time and transportation time. These definitions were used for a detailed time analysis of the in-hospital mortality of AHF patients. Statistical comparisons of continuous variables were performed with the use of Student t test, and discrete variables were compared with the use of the c2 test. Stepwise multiple logistic regression analysis was performed to predict in-hospital mortality rate. Stability of the model was checked every time a variable was eliminated until all statistically nonsignificant variables (P ! .10) had been eliminated from the model. Furthermore, because low SBP on arrival to ER was one of the predictors for in-hospital mortality,9 we further divided the patients into 3 groups according to their systolic blood pressure (SBP) values on presentation in accordance with the clinical scenario (CS) system proposed by Mebazaa et al10: SBP !90, 90e130, and O130 mm Hg. All probability values were 2 tailed, and values of P ! .05 were considered to be statistically significant.
The TCN database is an ongoing multicenter registry that prospectively collects information of emergency admissions to acute cardiac care facilities.8 The TCN database aimed to describe the demographic and clinical characteristics of patients hospitalized with acute cardiovascular disease. All patients admitted to the cardiac care facilities whose information had been catalogued by TCN were eligible for participation into the study. By November 2009, 67 hospitals, serving a population of 1.3 million individuals in the metropolitan Tokyo area, had been included in the TCN registry. A standard data set was established with written definitions and uniform data entry and transmission requirements. Informed consents were not required, because all of the data was anonymously catalogued. Data collection was performed via individual chart review by trained data collection personnel. The quality of submitted data is maintained through mechanisms including point-of-entry and annual data quality checks. No extramural funding was used to support this work. Each TCN hospital is accredited by the Metropolitan Tokyo Government and participates in the Tokyo citywide system of acute cardiac care (acute myocardial infarction, unstable angina, arrhythmia, acute heart failure, aortic dissection, and pulmonary embolism). The first responders provide basic life support facilities with automatic external defibrillator capability. Prehospital triage, treatment, and transport protocols are uniform within city limits. This study was approved by the Institutional Review Board of Keio University Hospital. Patients and Data Collection In our analysis, AHF was defined as rapid onset or change in the signs and symptoms of heart failure requiring urgent therapy and admission to a coronary care unit or cardiac telemetry unit. The clinical diagnosis of AHF was made by individual cardiologists at each institution. There was no specific treatment protocol for AHF in the TCN hospitals. The patients were treated on the basis of the Japanese Circulation Society (JCS) and ACC/AHA guidelines for the diagnosis and treatment of AHF. From 2005 to 2006, 2,205 consecutive AHF patients (ambulatory and EMS admissions) were identified. Most of the data were complete information except for the time from the onset of symptoms to arrival at the hospital, which could not be calculated in w35% of the cases; those cases were excluded from the analysis. Patients with acute coronary syndrome (ACS) also were excluded from this analysis. Consequently, data of 1,218 emergency transfers who were brought to the hospital via ambulance with complete information regarding the transportation time were analyzed. The following data on AHF patients were collected: 1) initial vital signs and symptoms in the ER, such as systolic blood pressure (SBP), SpO2, heart rate, altered metal status, dyspnea, and New York Heart Association (NYHA) or Killip classification; 2) left ventricular ejection fraction (EF) on admission; 3) etiology of heart failure; 4) patients’ background data; and 5) in-hospital mortality rate. The prehospital time interval was divided into 2 partsdthe time from the onset of heart failure symptoms to the arrival of the EMS to the patient’s residence (response
Statistical Analysis
Results Patient Demographics
The average age of patients was 76.1 6 11.5 years, and 54.1% of all patients were men (Table 1). Dyspnea is a major symptom of AHF, and it was present in 84.9% of all patients. Altered mental state, defined as Japan Coma Scale of $1, was seen in 22.1%. The etiology of AHF was determined to be hypertensive heart disease, valvular heart disease, cardiomyopathy, and previous myocardial infarction in 28.7%, 20.4%, 17.8%, and 24.9% of the patients, respectively. EF was preserved in 30.5% (EF $45%) and decreased in 67.8% (EF !45%) of the patients. On arrival, 22.2% of the patients were NYHA functional class III and 6.2% NYHA functional class IV. Furthermore, 44% of the patients were Killip grade 3 and 8.3% Killip grade 4, which is equivalent to cardiogenic shock. The SBP of most patients on ER arrival was O130 mm Hg (72%). The SBP ranged from 90 to 130 mm Hg in 20.1% of the patients and !90 mm Hg in 2.9% of the patients. Prehospital Time Interval and Outcomes
The overall in-hospital mortality rate was 6.0%. The median response time was 64 minutes (interquartile range [IQR] 26e205 minutes), and the transportation time was 27 minutes (IQR 9e78 minutes). Patients whose response time was !30 minutes presented with higher NYHA functional class and altered mental status and were more frequently found to have etiology of hypertensive heart disease (Table 1). Patients with response time of O30 minutes tended to present ischemic or nonischemic cardiomyopathy. The in-hospital mortality rate between the 2 patient groupsdresponse time of !30 minutes and
744 Journal of Cardiac Failure Vol. 17 No. 9 September 2011 Table 1. Characteristics of Patients With Acute Heart Failure in Relation to Response Time Variable Male (%) JSC $1 (%) Blood pressure SBP #90 mm Hg (%) SBP 90e130 mm Hg (%) Cardiac arrest (%) Chest pain on presentation (%) Dyspnea on presentation (%) Bundle branch block (%) Previous myocardial infarction (%) Arrhythmic disorders (%) Hypertensive heart disease (%) Valvular heart disease (%) Cardiomyopathy (%) DCM (%) ICM (%) HCM (%) Left ventricular function (%) EF !30% EF 30%e45% EF 45%e60% NYHA IV (%) Death (%)
Overall (n 5 1,109)
Response Time #30 min (n 5 474)
Response Time O30 min (n 5 744)
P Value
54.1 22.1
53.6 28.7
54.4 17.9
.409 !.001
2.9 20.1 0.4 8.6 84.9 4.4 24.9 4.3 28.7 20.4 17.8 6.7 5.4 2.3
3.4 18.4 0.4 8.0 84.0 5.9 25.3 3.8 31.9 21.5 15.6 5.3 4.2 3.0
2.6 21.2 0.4 9.0 85.5 3.4 24.6 4.6 26.6 19.8 19.2 7.5 6.2 1.9
.252 .125 .644 .312 .261 .025 .414 .310 .028 .251 .063 .076 .088 .154
27.2 40.6 30.5 6.2 6.0
28.3 38.2 31.2 7.6 6.3
26.5 42.2 30.1 5.2 5.8
.267 .091 .363 .062 .391
JCS, Japan Coma Scale; SBP, systolic blood pressure; DCM, dilated cardiomyopathy; ICM, ischemic cardiomyopathy; HCM, hypertrophic cardiomyopathy; EF, ejection fraction; NYHA, New York Heart Association functional class.
response time O30 minutesddid not exhibit significant differences (6.3% vs 5.8%; P 5 .09). The risk-adjusted mortality did not correlate well with the response time, but the mortality increased with transportation time (Fig. 1). As demonstrated in the Figure 1, these 2 time intervals have different distributions and clinical implications and could not be considered as simple continuous or ordinary values. Therefore, we dichotomized the time intervals according to the clinically relevant response and transfer times of 30 and 45 minutes, respectively. As a result, patients whose transfer times to the medical centers exceeded 45 minutes were at higher risk for in-hospital mortality (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.17e4.31; Table 2). Other clinical parameters associated with in-hospital mortality were low SBP on ER arrival (SBP !90 mm Hg: OR 2.90, 95% CI 1.09e7.69; SBP 90e130 mm Hg: OR 3.28, 95% CI 1.95e5.51), altered mental status (defined as Japan Coma Scale $1), and age. Notably, Killip classification and decreased EF on arrival were not associated with short-term mortality. Discussion The TCN database is the first large multicenter registry in Japan that collects data of patients with acute cardiovascular disease. AHF is one of the most frequently encountered cardiovascular conditions and can seriously affect the patient’s prognosis.1,3,11 The overall in-hospital mortality rate was 6.0%, which was slightly higher than AHF registries in other Western countries.5,7 This is probably because our database contained a higher number of older patients,
reflecting the relatively higher proportion of aged individuals in Japan. In this study, our primary finding was that EMS-to-door time of O45 minutes is a significant predictor of in-hospital death. This result suggests that early initiation of treatment may improve the short-term outcome in AHF patients, which is similar to results reported in previous studies.11 An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) indicated that the time to initiation of the AHF therapies affected the length of hospital stay as well as the in-hospital mortality.12 However, AHF treatments were often initiated in !8 hours after presentation, and the mean times to intravenous diuretics and vasoactive therapy were 8.1 and 22.8 hours, respectively.13,14 Furthermore, a majority of the AHF patients transfered by EMS were in the state of circulatory insufficiency, respiratory acidosis, and consciousness disturbance. Because the EMTs in Japan are allowed only to monitor the patients, any transportation delay leads to delays in aggressive respiratory management, including noninvasive ventilation or administration of vasodilators and diuretics or catecholamines; this might have had a stronger impact in the present cohort. There are many acute care facilities in Tokyo, and the distance from the Emergency Department is hardly a problem. Notorious traffic delay is also not of much concern, because vehicles would usually open the street for ambulances; in fact, data from Tokyo Fire Department reported that the median time from calling EMS to arrival at the site was 6 minutes. However, the triage system is encountering a systemic issue, because the nationwide government insurance system is leading to congestion within hospitals;
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Fig. 1. Crude and adjusted mortality based on (A) response and (B) transportation times.
this is reflected in transportation time (median 27 minutes) that is more than fourfold the time from calling EMS to arrival at the site. Shuttling of patients across multiple hospitals (‘‘barrel-rolling’’) during emergency transportation is an issue in Japan. The generalized application of the present Table 2. Predictors of In-Hospital Mortality as a Result of Logistic Regression Modeling OR EMS to ER O45 min Symptom onset to call O3 h Call to EMS arrival O15 min Male subjects SBP !90 mm Hg SBP 90e130 mm Hg Killip 4 JCS $1 Valve disease Age classification* EF !30% EF $45% Non-CCU admission
2.243 1.614 1.325 0.726 2.904 3.280 1.965 2.189 0.831 1.501 1.086 0.687 0.874
95% CI 1.17 0.904 0.436 0.421 1.097 1.952 0.843 1.264 0.442 1.220 0.570 0.370 0.423
4.313 2.881 4.025 1.253 7.688 5.514 4.580 3.792 1.562 1.847 2.071 1.276 1.808
P Value .015 .105 .620 .255 .032 !.001 .118 .005 .565 !.001 .802 .235 .716
OR, odds ratio; CI, confidence interval; EMS, emergency medical services; ER, emergency room; CCU, coronary care unit; other abbreviations as in Table 1. *Odds ratio of age was calculated for a 5-year increment.
result may be limited, but we think that this manuscript has important political implications in large metropolitan areas encountering similar issues. A majority of the patients in our cohort presented with dyspnea (85%), which was higher than in similar studies with Western registries, such as ADHERE (w70%).15 Because our cohort comprised only patients admitted via EMS, they may represent a cross-section of AHF patients with relatively severe symptoms requiring the call for medical attention. In addition, the chief complaint in the TCN registry had to be selected from 4 available options: dyspnea, chest pain, altered mental status, and other symptoms of heart failure. Limited choices of these presenting symptoms might have led to overrepresentation of typical AHF complaints such as dyspnea. Finally, dyspnea remains the most common and disturbing symptom in AHF, but there is no current standardized measurement for it. Quantitative dyspnea scaling is a good option to eliminate such a bias and should be considered in future studies. In the present analysis, we excluded patients with ACS; however, almost 10% of the patients in this registry had chest pain on presentation. There may have been an overrepresentation of each of the presenting symptoms, because the chief complaint had to be selected from only 4 available
746 Journal of Cardiac Failure Vol. 17 No. 9 September 2011 options in the registry. Furthermore, although ACS was excluded from our analysis, 24.9% of the patients had a history of coronary artery disease and may have had chest pain on admission (without elevated biomarker or electrocardiogram changes, which would have excluded them as having ACS in the present study). Finally, Asians are known to have a higher rate of microvascular dysfunction associated with chest pain in AHF patients. The risk-adjusted mortality did not simply increase with response time. There seemed to be 2 mortality peaks in Figure 1A. The first peak was observed in patients who took 15e30 minutes from the time of symptom onset to EMS arrival, and the second peak was seen in patients whose symptom onset to EMS arrival took O30 minutes. The response time might depend on the type of AHF, ie, AHF with acute onset and elevated blood pressure at presentation usually without systemic congestion (so-called flash pulmonary edema), as defined in CS1, or AHF with gradual development and normal blood pressure usually with systemic congestion, as defined in CS2. We hypothesized that the 2 peaks represented these 2 types of AHF: Patients who suffered from flash pulmonary edema might have called EMS earlier, and patients whose symptoms developed gradually might have called EMS later. The peak of these syndromes seemed to be separated by a time interval of 30 minutes. Interestingly, the patients who called EMS within 30 minutes of symptom onset differed from those who called EMS later, exhibiting worse altered mental statues, high NYHA classification, and heart failure etiology of hypertensive heart failure. Earlier call placed to the EMS and earlier transportation of patients to the ER may lead to earlier treatment and more favorable in-hospital outcome, but it should be emphasized that the overuse of EMS has also become a major issue in Japan. EMS is frequently used for relatively minor medical problems, leading to EMS dispatch every 6 minutes, and a national survey in 2007 reported that w1 in every 26 citizens has availed themselves of EMS. Furthermore, of the severely diseased patients who were taken to the ER via emergency transportation, 3.6% were rejected admission into the emergency facilities O3 times. Thus, a balanced approach, considering the social need of emergency care, is necessary to implement practical early-phase management in patients presenting with AHF.
Study Limitations
The present analysis of the TCN database is limited by a number of factors. The data were obtained as the result of an observational study, and unmeasured factors may have influenced the clinical outcome. Also, the registry was geographically limited to the metropolitan Tokyo area and may not be applicable to other areas in Japan, particularly in the rural areas. In addition, not all the AHF patients are transfered to the ER by EMS; some patients presented by themselves to outpatient clinics.
We used in-hospital mortality as our dependant variable. The use of 30-day mortality has been proposed to ensure fair assessment of all hospitals and to prevent differences in the transfer rates or variations in duration of stay. Numerous studies have demonstrated the problems with using in-hospital mortality as opposed to 30-day mortality as an outcome, because the former is strongly affected by the duration of stay. However, in-hospital mortality is an unambiguous factor and is usually tabulated accurately. Furthermore, because Japanese hospitals permit longer hospital stays for AHF patients, with an extremely low rate of interhospital transfers, owing to social insurance coverage, we think that this longer hospital stay enables complete follow-up of our patients and lessens the above bias. The average hospital stay for AHF in Japan is w3 weeks compared with 6 days in the US. Further, the NYHA functional class is IeII in O90% of the patients at the time of discharge in Japan.16,17 Conclusions The transportation time was independently associated with risk-adjusted mortality. In Japanese society, delay in the prehospital transportation time of EMS has been noted, and efforts should be implemented to reduce the EMS transfer time to improve outcomes in AHF patients. Disclosures None.
References 1. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007; 50:768e77. 2. Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958e68. 3. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol 2006; 47:76e84. 4. Olson DW, LaRochelle J, Fark D, Aprahamian C, Aufderheide TP, Mateer JR, et al. EMT-defibrillation: the Wisconsin experience. Ann Emerg Med 1989;18:806e11. 5. Thompson RG, Hallstrom AP, Cobb LA. Bystander-initiated cardiopulmonary resuscitation in the management of ventricular fibrillation. Ann Intern Med 1979;90:737e40. 6. Brodie BR, Grines CL, Stone GW. Effect of door-to-balloon time on patient mortality. J Am Coll Cardiol 2006;48:2600. author reply 2601. 7. Magid DJ, Wang Y, Herrin J, McNamara RL, Bradley EH, Curtis JP, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA 2005;294:803e12.
Pre-Hospital Time Interval and Acute Heart Failure 8. Tokyo CCU Network Scientific Committee. Latest management and outcomes of major pulmonary embolism in the cardiovascular disease early transport system: Tokyo CCU Network. Circ J 2010;74:289e93. 9. Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor CM, She L, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217e26. 10. Mebazaa A, Gheorghiade M, Pina IL, Harjola VP, Hollenberg SM, Follath F, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008;36(1 Suppl):S129e39. 11. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557e73. 12. Emerman CL. Treatment of the acute decompensation of heart failure: efficacy and pharmacoeconomics of early initiation of therapy in the emergency department. Rev Cardiovasc Med 2003;4(Suppl 7): S13e20. 13. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57e64. 14. 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;52:347e56. 15. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209e16. 16. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, et al. Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 2009;73:1893e900. 17. Sato N, Kajimoto K, Asai K, Mizuno M, Minami Y, Nagashima M. Acute Decompensated Heart Failure Syndromes (ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, and preliminary data. Am Heart J 2010;159:949e55.e1.
Appendix 1 Participating Hospitals and Leading Members of the Tokyo Cardiac Care Unit Network Ayase Heart Hospital, Imun Tei; Edogawa Hospital, Yoji Oohira; Hakujikai Memorial Hospital, Kunio Tanaka; Higashiyamato Hospital, Masao Kawada; Ikegami General Hospital, Takao Machimura; IMS Katsushika Heart Center, Masayoshi Sakakibara; Toyama Hospital, International Medical Center of Japan, Michiaki Hiroe; Itabashi Chuo Medical Center, Hiroshi Ota; Japanese Red Cross Medical
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Center, Akihiko Aoyagi; Jikei University Aoto Hospital, Shingo Seki; Jikei University Daisan Hospital, Takahiro Shibata; Jikei University Hospital, Michihiro Yoshimura; Juntendo University Hospital, Hiroyuki Daita; Kanto Central Hospital, Hiroshi Ikenouchi; Kawakita General Hospital, Yoichi Sugimura; Keio University Hospital, Tsutomu Yoshikawa; Kohsei Chuo General Hospital, Akio Hirai; Kosei General Hospital, Masao Kawaguchi; Kyorin University Hospital, Hideo Yoshino; Mishuku Hospital, Akimi Uehata; Mitsui Memorial Hospital, Kazuhiro Hara; Musashino Red Cross Hospital, Tohru Obayashi; Disaster Medical Center, Yasuhiro Satoh; National Hospital Organization, Tokyo Medical Center, Yukihiko Momiyama; Nihon University Itabashi Hospital, Tadateru Takayama; Nihon University Nerima Hikarigaoka Hospital, Seiji Fukushima; Nippon Medical School Hospital, Keiji Tanaka; Nippon Medical School Tama-Nagayama Hospital, Hirotsugu Atarashi; Nishiarai Hospital, Katsumi Saito; Nishitokyo Central General Hospital, Hiroyuki Suesada; Kanto Medical Center NTT EC, Satoshi Ohnishi; Ome Municipal General Hospital, Shigeo Shimizu; Sakakibara Heart Institute, Tetsuya Sumiyoshi; Senpo Tokyo Takanawa Hospital, Masato Yamamoto; Showa General Hospital, Yuji Kira; Showa University Hospital, Youichi Kobayashi; Social Insurance Central General Hospital, Makoto Noda; St. Luke’s Hospital, Yuji Kira; Showa University Hospital, Nihon University Hospital, Ken Nagao; Tama Nambu Chiiki Hospital, Hiroyuki Takata; Teikyo University Hospital, Takaaki Isshiki; The Cardiovascular Institute, Akira Koike; Tobu Chiiki Hospital, Takashi Tamura; Toho University Omori Medical Center, Nobuya Koyama; Toho University Ohashi Medical Center, Masato Nakamura; Tokai University Hachioji-Hospital, Yoshinori Kobayashi; Tokyo Kosei Nenkin Hospital, Seiji Ayabe; Tokyo Medical and Dental University, Mitsuaki Isobe; Tokyo Medical University Hospital, Akira Yamashina; Tokyo Medical University, Hachioji Medical Center, Hiroshi Kobayashi; Tokyo Metropolitan Bokutoh General Hospital, Ichiro Kubo; Tokyo Metropolitan Fuchu Hospital, Tetsuro Ueda; Tokyo Metropolitan Geriatric Hospital, Kazumasa Harada; Tokyo Metropolitan Hiroo Hospital, Harumizu Sakurada; Tokyo Metropolitan Police Hospital, Tetsuro Shirai; Tokyo Rinkai Hospital, Toru Kono; Saiseikai Central Hospital, Hideo Mitamura; Tokyo Women’s Medical University Hospital, Nobuhisa Hagiwara; Tokyo Women’s Medical University Medical Center East, Kuniaki Otsuka; Toranomon Hospital, Sugao Ishiwata; Tokyo Metropolitan Health and Medical Treatment Corporation, Toshima Hospital, Takashi Shibui; University of Tokyo Hospital, Ryozo Nagai.
Association Between Prehospital Time Interval and Short-Term Outcome in Acute Heart Failure Patients MASASHI TAKAHASHI, MD, SHUN KOHSAKA, MD, HIROAKI MIYATA, PhD, TSUTOMU YOSHIKAWA, MD, ATSUTOSHI TAKAGI, MD, KAZUMASA HARADA, MD, TAKAMICHI MIYAMOTO, MD, TETSUO SAKAI, MD, KEN NAGAO, MD, NAOKI SATO, MD, AND MORIMASA TAKAYAMA, MD, FOR TOKYO CCU NETWORK COUNCIL Tokyo, Japan
ABSTRACT Background: Acute heart failure (AHF) is one of the most frequently encountered cardiovascular conditions that can seriously affect the patient’s prognosis. However, the importance of early triage and treatment initiation in the setting of AHF has not been recognized. Methods and Results: The Tokyo Cardiac Care Unit Network Database prospectively collected information of emergency admissions to acute cardiac care facilities in 2005e2007 from 67 participating hospitals in the Tokyo metropolitan area. We analyzed records of 1,218 AHF patients transported to medical centers via emergency medical services (EMS). AHF was defined as rapid onset or change in the signs and symptoms of heart failure, resulting in the need for urgent therapy. Patients with acute coronary syndrome were excluded from this analysis. Logistic regression analysis was performed to calculate the risk-adjusted inhospital mortality. A majority of the patients were elderly (76.1 6 11.5 years old) and male (54.1%). The overall in-hospital mortality rate was 6.0%. The median time interval between symptom onset and EMS arrival (response time) was 64 minutes (interquartile range [IQR] 26e205 minutes), and that between EMS arrival and ER arrival (transportation time) was 27 minutes (IQR 9e78 minutes). The riskadjusted mortality increased with transportation time, but did not correlate with the response time. Those who took O45 minutes to arrive at the medical centers were at a higher risk for in-hospital mortality (odds ratio 2.24, 95% confidence interval 1.17e4.31; P 5 .015). Conclusions: Transportation time correlated with risk-adjusted mortality, and steps should be taken to reduce the EMS transfer time to improve the outcome in AHF patients. (J Cardiac Fail 2011;17:742e747) Key Words: Network, heart failure, ambulance.
Acute heart failure (AHF) is one of the most frequently encountered cardiovascular conditions and can seriously affect the patient’s prognosis.1e3 However, there is little additional guidance on how emergency medical services (EMS) should optimize their time before hospital arrival. In the acute settings of other cardiovascular disease, particularly ischemic conditions, reducing the time until initial medical care is important for improving the prognosis. For example,
immediate cardiopulmonary resuscitation and defibrillation for ventricular tachycardia/fibrillation contribute to improved prognosis in patients with sudden cardiac arrest.4,5 Timely coronary reperfusion by primary percutaneous coronary intervention (PCI) is the cornerstone of modern management in the case of high-risk acute coronary syndrome; both symptom-to-reperfusion and door-to-balloon times are important predictors of ST-segment elevation myocardial infarction (STEMI).6,7 Current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) recommend that the interval from the first medical contact to PCI be !90 minutes for individuals experiencing STEMI. Early and appropriate intervention to AHF patients may aid in improving the short-term outcome of AHF. The present study aimed to describe the preehospital system time intervals from symptom onset to Emergency Room (ER) arrival to assess the relationship between the time intervals
From the Tokyo CCU Network Scientific Committee, Tokyo, Japan. Manuscript received December 17, 2010; revised manuscript received April 17, 2011; revised manuscript accepted May 9, 2011. Reprint requests: Shun Kohsaka, MD, Department of Cardiology, Keio University Hospital, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] See page 746 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.05.005
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and in-hospital mortality and to derive theoretic benchmarks for system time intervals in AHF patients admitted in hospitals belonging to the Tokyo Cardiac Care Unit Network (TCN; Appendix 1).
time) and the time for transportation to the ER via ambulance (transportation time). Time until triage at the ER was not measured in this registry.
Methods
The present analysis was designed to compare the relationship between prehospital time interval and in-hospital mortality. The prehospital time interval was divided into response time and transportation time. These definitions were used for a detailed time analysis of the in-hospital mortality of AHF patients. Statistical comparisons of continuous variables were performed with the use of Student t test, and discrete variables were compared with the use of the c2 test. Stepwise multiple logistic regression analysis was performed to predict in-hospital mortality rate. Stability of the model was checked every time a variable was eliminated until all statistically nonsignificant variables (P ! .10) had been eliminated from the model. Furthermore, because low SBP on arrival to ER was one of the predictors for in-hospital mortality,9 we further divided the patients into 3 groups according to their systolic blood pressure (SBP) values on presentation in accordance with the clinical scenario (CS) system proposed by Mebazaa et al10: SBP !90, 90e130, and O130 mm Hg. All probability values were 2 tailed, and values of P ! .05 were considered to be statistically significant.
The TCN database is an ongoing multicenter registry that prospectively collects information of emergency admissions to acute cardiac care facilities.8 The TCN database aimed to describe the demographic and clinical characteristics of patients hospitalized with acute cardiovascular disease. All patients admitted to the cardiac care facilities whose information had been catalogued by TCN were eligible for participation into the study. By November 2009, 67 hospitals, serving a population of 1.3 million individuals in the metropolitan Tokyo area, had been included in the TCN registry. A standard data set was established with written definitions and uniform data entry and transmission requirements. Informed consents were not required, because all of the data was anonymously catalogued. Data collection was performed via individual chart review by trained data collection personnel. The quality of submitted data is maintained through mechanisms including point-of-entry and annual data quality checks. No extramural funding was used to support this work. Each TCN hospital is accredited by the Metropolitan Tokyo Government and participates in the Tokyo citywide system of acute cardiac care (acute myocardial infarction, unstable angina, arrhythmia, acute heart failure, aortic dissection, and pulmonary embolism). The first responders provide basic life support facilities with automatic external defibrillator capability. Prehospital triage, treatment, and transport protocols are uniform within city limits. This study was approved by the Institutional Review Board of Keio University Hospital. Patients and Data Collection In our analysis, AHF was defined as rapid onset or change in the signs and symptoms of heart failure requiring urgent therapy and admission to a coronary care unit or cardiac telemetry unit. The clinical diagnosis of AHF was made by individual cardiologists at each institution. There was no specific treatment protocol for AHF in the TCN hospitals. The patients were treated on the basis of the Japanese Circulation Society (JCS) and ACC/AHA guidelines for the diagnosis and treatment of AHF. From 2005 to 2006, 2,205 consecutive AHF patients (ambulatory and EMS admissions) were identified. Most of the data were complete information except for the time from the onset of symptoms to arrival at the hospital, which could not be calculated in w35% of the cases; those cases were excluded from the analysis. Patients with acute coronary syndrome (ACS) also were excluded from this analysis. Consequently, data of 1,218 emergency transfers who were brought to the hospital via ambulance with complete information regarding the transportation time were analyzed. The following data on AHF patients were collected: 1) initial vital signs and symptoms in the ER, such as systolic blood pressure (SBP), SpO2, heart rate, altered metal status, dyspnea, and New York Heart Association (NYHA) or Killip classification; 2) left ventricular ejection fraction (EF) on admission; 3) etiology of heart failure; 4) patients’ background data; and 5) in-hospital mortality rate. The prehospital time interval was divided into 2 partsdthe time from the onset of heart failure symptoms to the arrival of the EMS to the patient’s residence (response
Statistical Analysis
Results Patient Demographics
The average age of patients was 76.1 6 11.5 years, and 54.1% of all patients were men (Table 1). Dyspnea is a major symptom of AHF, and it was present in 84.9% of all patients. Altered mental state, defined as Japan Coma Scale of $1, was seen in 22.1%. The etiology of AHF was determined to be hypertensive heart disease, valvular heart disease, cardiomyopathy, and previous myocardial infarction in 28.7%, 20.4%, 17.8%, and 24.9% of the patients, respectively. EF was preserved in 30.5% (EF $45%) and decreased in 67.8% (EF !45%) of the patients. On arrival, 22.2% of the patients were NYHA functional class III and 6.2% NYHA functional class IV. Furthermore, 44% of the patients were Killip grade 3 and 8.3% Killip grade 4, which is equivalent to cardiogenic shock. The SBP of most patients on ER arrival was O130 mm Hg (72%). The SBP ranged from 90 to 130 mm Hg in 20.1% of the patients and !90 mm Hg in 2.9% of the patients. Prehospital Time Interval and Outcomes
The overall in-hospital mortality rate was 6.0%. The median response time was 64 minutes (interquartile range [IQR] 26e205 minutes), and the transportation time was 27 minutes (IQR 9e78 minutes). Patients whose response time was !30 minutes presented with higher NYHA functional class and altered mental status and were more frequently found to have etiology of hypertensive heart disease (Table 1). Patients with response time of O30 minutes tended to present ischemic or nonischemic cardiomyopathy. The in-hospital mortality rate between the 2 patient groupsdresponse time of !30 minutes and
744 Journal of Cardiac Failure Vol. 17 No. 9 September 2011 Table 1. Characteristics of Patients With Acute Heart Failure in Relation to Response Time Variable Male (%) JSC $1 (%) Blood pressure SBP #90 mm Hg (%) SBP 90e130 mm Hg (%) Cardiac arrest (%) Chest pain on presentation (%) Dyspnea on presentation (%) Bundle branch block (%) Previous myocardial infarction (%) Arrhythmic disorders (%) Hypertensive heart disease (%) Valvular heart disease (%) Cardiomyopathy (%) DCM (%) ICM (%) HCM (%) Left ventricular function (%) EF !30% EF 30%e45% EF 45%e60% NYHA IV (%) Death (%)
Overall (n 5 1,109)
Response Time #30 min (n 5 474)
Response Time O30 min (n 5 744)
P Value
54.1 22.1
53.6 28.7
54.4 17.9
.409 !.001
2.9 20.1 0.4 8.6 84.9 4.4 24.9 4.3 28.7 20.4 17.8 6.7 5.4 2.3
3.4 18.4 0.4 8.0 84.0 5.9 25.3 3.8 31.9 21.5 15.6 5.3 4.2 3.0
2.6 21.2 0.4 9.0 85.5 3.4 24.6 4.6 26.6 19.8 19.2 7.5 6.2 1.9
.252 .125 .644 .312 .261 .025 .414 .310 .028 .251 .063 .076 .088 .154
27.2 40.6 30.5 6.2 6.0
28.3 38.2 31.2 7.6 6.3
26.5 42.2 30.1 5.2 5.8
.267 .091 .363 .062 .391
JCS, Japan Coma Scale; SBP, systolic blood pressure; DCM, dilated cardiomyopathy; ICM, ischemic cardiomyopathy; HCM, hypertrophic cardiomyopathy; EF, ejection fraction; NYHA, New York Heart Association functional class.
response time O30 minutesddid not exhibit significant differences (6.3% vs 5.8%; P 5 .09). The risk-adjusted mortality did not correlate well with the response time, but the mortality increased with transportation time (Fig. 1). As demonstrated in the Figure 1, these 2 time intervals have different distributions and clinical implications and could not be considered as simple continuous or ordinary values. Therefore, we dichotomized the time intervals according to the clinically relevant response and transfer times of 30 and 45 minutes, respectively. As a result, patients whose transfer times to the medical centers exceeded 45 minutes were at higher risk for in-hospital mortality (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.17e4.31; Table 2). Other clinical parameters associated with in-hospital mortality were low SBP on ER arrival (SBP !90 mm Hg: OR 2.90, 95% CI 1.09e7.69; SBP 90e130 mm Hg: OR 3.28, 95% CI 1.95e5.51), altered mental status (defined as Japan Coma Scale $1), and age. Notably, Killip classification and decreased EF on arrival were not associated with short-term mortality. Discussion The TCN database is the first large multicenter registry in Japan that collects data of patients with acute cardiovascular disease. AHF is one of the most frequently encountered cardiovascular conditions and can seriously affect the patient’s prognosis.1,3,11 The overall in-hospital mortality rate was 6.0%, which was slightly higher than AHF registries in other Western countries.5,7 This is probably because our database contained a higher number of older patients,
reflecting the relatively higher proportion of aged individuals in Japan. In this study, our primary finding was that EMS-to-door time of O45 minutes is a significant predictor of in-hospital death. This result suggests that early initiation of treatment may improve the short-term outcome in AHF patients, which is similar to results reported in previous studies.11 An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) indicated that the time to initiation of the AHF therapies affected the length of hospital stay as well as the in-hospital mortality.12 However, AHF treatments were often initiated in !8 hours after presentation, and the mean times to intravenous diuretics and vasoactive therapy were 8.1 and 22.8 hours, respectively.13,14 Furthermore, a majority of the AHF patients transfered by EMS were in the state of circulatory insufficiency, respiratory acidosis, and consciousness disturbance. Because the EMTs in Japan are allowed only to monitor the patients, any transportation delay leads to delays in aggressive respiratory management, including noninvasive ventilation or administration of vasodilators and diuretics or catecholamines; this might have had a stronger impact in the present cohort. There are many acute care facilities in Tokyo, and the distance from the Emergency Department is hardly a problem. Notorious traffic delay is also not of much concern, because vehicles would usually open the street for ambulances; in fact, data from Tokyo Fire Department reported that the median time from calling EMS to arrival at the site was 6 minutes. However, the triage system is encountering a systemic issue, because the nationwide government insurance system is leading to congestion within hospitals;
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Fig. 1. Crude and adjusted mortality based on (A) response and (B) transportation times.
this is reflected in transportation time (median 27 minutes) that is more than fourfold the time from calling EMS to arrival at the site. Shuttling of patients across multiple hospitals (‘‘barrel-rolling’’) during emergency transportation is an issue in Japan. The generalized application of the present Table 2. Predictors of In-Hospital Mortality as a Result of Logistic Regression Modeling OR EMS to ER O45 min Symptom onset to call O3 h Call to EMS arrival O15 min Male subjects SBP !90 mm Hg SBP 90e130 mm Hg Killip 4 JCS $1 Valve disease Age classification* EF !30% EF $45% Non-CCU admission
2.243 1.614 1.325 0.726 2.904 3.280 1.965 2.189 0.831 1.501 1.086 0.687 0.874
95% CI 1.17 0.904 0.436 0.421 1.097 1.952 0.843 1.264 0.442 1.220 0.570 0.370 0.423
4.313 2.881 4.025 1.253 7.688 5.514 4.580 3.792 1.562 1.847 2.071 1.276 1.808
P Value .015 .105 .620 .255 .032 !.001 .118 .005 .565 !.001 .802 .235 .716
OR, odds ratio; CI, confidence interval; EMS, emergency medical services; ER, emergency room; CCU, coronary care unit; other abbreviations as in Table 1. *Odds ratio of age was calculated for a 5-year increment.
result may be limited, but we think that this manuscript has important political implications in large metropolitan areas encountering similar issues. A majority of the patients in our cohort presented with dyspnea (85%), which was higher than in similar studies with Western registries, such as ADHERE (w70%).15 Because our cohort comprised only patients admitted via EMS, they may represent a cross-section of AHF patients with relatively severe symptoms requiring the call for medical attention. In addition, the chief complaint in the TCN registry had to be selected from 4 available options: dyspnea, chest pain, altered mental status, and other symptoms of heart failure. Limited choices of these presenting symptoms might have led to overrepresentation of typical AHF complaints such as dyspnea. Finally, dyspnea remains the most common and disturbing symptom in AHF, but there is no current standardized measurement for it. Quantitative dyspnea scaling is a good option to eliminate such a bias and should be considered in future studies. In the present analysis, we excluded patients with ACS; however, almost 10% of the patients in this registry had chest pain on presentation. There may have been an overrepresentation of each of the presenting symptoms, because the chief complaint had to be selected from only 4 available
746 Journal of Cardiac Failure Vol. 17 No. 9 September 2011 options in the registry. Furthermore, although ACS was excluded from our analysis, 24.9% of the patients had a history of coronary artery disease and may have had chest pain on admission (without elevated biomarker or electrocardiogram changes, which would have excluded them as having ACS in the present study). Finally, Asians are known to have a higher rate of microvascular dysfunction associated with chest pain in AHF patients. The risk-adjusted mortality did not simply increase with response time. There seemed to be 2 mortality peaks in Figure 1A. The first peak was observed in patients who took 15e30 minutes from the time of symptom onset to EMS arrival, and the second peak was seen in patients whose symptom onset to EMS arrival took O30 minutes. The response time might depend on the type of AHF, ie, AHF with acute onset and elevated blood pressure at presentation usually without systemic congestion (so-called flash pulmonary edema), as defined in CS1, or AHF with gradual development and normal blood pressure usually with systemic congestion, as defined in CS2. We hypothesized that the 2 peaks represented these 2 types of AHF: Patients who suffered from flash pulmonary edema might have called EMS earlier, and patients whose symptoms developed gradually might have called EMS later. The peak of these syndromes seemed to be separated by a time interval of 30 minutes. Interestingly, the patients who called EMS within 30 minutes of symptom onset differed from those who called EMS later, exhibiting worse altered mental statues, high NYHA classification, and heart failure etiology of hypertensive heart failure. Earlier call placed to the EMS and earlier transportation of patients to the ER may lead to earlier treatment and more favorable in-hospital outcome, but it should be emphasized that the overuse of EMS has also become a major issue in Japan. EMS is frequently used for relatively minor medical problems, leading to EMS dispatch every 6 minutes, and a national survey in 2007 reported that w1 in every 26 citizens has availed themselves of EMS. Furthermore, of the severely diseased patients who were taken to the ER via emergency transportation, 3.6% were rejected admission into the emergency facilities O3 times. Thus, a balanced approach, considering the social need of emergency care, is necessary to implement practical early-phase management in patients presenting with AHF.
Study Limitations
The present analysis of the TCN database is limited by a number of factors. The data were obtained as the result of an observational study, and unmeasured factors may have influenced the clinical outcome. Also, the registry was geographically limited to the metropolitan Tokyo area and may not be applicable to other areas in Japan, particularly in the rural areas. In addition, not all the AHF patients are transfered to the ER by EMS; some patients presented by themselves to outpatient clinics.
We used in-hospital mortality as our dependant variable. The use of 30-day mortality has been proposed to ensure fair assessment of all hospitals and to prevent differences in the transfer rates or variations in duration of stay. Numerous studies have demonstrated the problems with using in-hospital mortality as opposed to 30-day mortality as an outcome, because the former is strongly affected by the duration of stay. However, in-hospital mortality is an unambiguous factor and is usually tabulated accurately. Furthermore, because Japanese hospitals permit longer hospital stays for AHF patients, with an extremely low rate of interhospital transfers, owing to social insurance coverage, we think that this longer hospital stay enables complete follow-up of our patients and lessens the above bias. The average hospital stay for AHF in Japan is w3 weeks compared with 6 days in the US. Further, the NYHA functional class is IeII in O90% of the patients at the time of discharge in Japan.16,17 Conclusions The transportation time was independently associated with risk-adjusted mortality. In Japanese society, delay in the prehospital transportation time of EMS has been noted, and efforts should be implemented to reduce the EMS transfer time to improve outcomes in AHF patients. Disclosures None.
References 1. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007; 50:768e77. 2. Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958e68. 3. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol 2006; 47:76e84. 4. Olson DW, LaRochelle J, Fark D, Aprahamian C, Aufderheide TP, Mateer JR, et al. EMT-defibrillation: the Wisconsin experience. Ann Emerg Med 1989;18:806e11. 5. Thompson RG, Hallstrom AP, Cobb LA. Bystander-initiated cardiopulmonary resuscitation in the management of ventricular fibrillation. Ann Intern Med 1979;90:737e40. 6. Brodie BR, Grines CL, Stone GW. Effect of door-to-balloon time on patient mortality. J Am Coll Cardiol 2006;48:2600. author reply 2601. 7. Magid DJ, Wang Y, Herrin J, McNamara RL, Bradley EH, Curtis JP, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA 2005;294:803e12.
Pre-Hospital Time Interval and Acute Heart Failure 8. Tokyo CCU Network Scientific Committee. Latest management and outcomes of major pulmonary embolism in the cardiovascular disease early transport system: Tokyo CCU Network. Circ J 2010;74:289e93. 9. Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor CM, She L, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217e26. 10. Mebazaa A, Gheorghiade M, Pina IL, Harjola VP, Hollenberg SM, Follath F, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008;36(1 Suppl):S129e39. 11. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557e73. 12. Emerman CL. Treatment of the acute decompensation of heart failure: efficacy and pharmacoeconomics of early initiation of therapy in the emergency department. Rev Cardiovasc Med 2003;4(Suppl 7): S13e20. 13. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57e64. 14. 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;52:347e56. 15. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209e16. 16. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, et al. Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 2009;73:1893e900. 17. Sato N, Kajimoto K, Asai K, Mizuno M, Minami Y, Nagashima M. Acute Decompensated Heart Failure Syndromes (ATTEND) registry. A prospective observational multicenter cohort study: rationale, design, and preliminary data. Am Heart J 2010;159:949e55.e1.
Appendix 1 Participating Hospitals and Leading Members of the Tokyo Cardiac Care Unit Network Ayase Heart Hospital, Imun Tei; Edogawa Hospital, Yoji Oohira; Hakujikai Memorial Hospital, Kunio Tanaka; Higashiyamato Hospital, Masao Kawada; Ikegami General Hospital, Takao Machimura; IMS Katsushika Heart Center, Masayoshi Sakakibara; Toyama Hospital, International Medical Center of Japan, Michiaki Hiroe; Itabashi Chuo Medical Center, Hiroshi Ota; Japanese Red Cross Medical
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Center, Akihiko Aoyagi; Jikei University Aoto Hospital, Shingo Seki; Jikei University Daisan Hospital, Takahiro Shibata; Jikei University Hospital, Michihiro Yoshimura; Juntendo University Hospital, Hiroyuki Daita; Kanto Central Hospital, Hiroshi Ikenouchi; Kawakita General Hospital, Yoichi Sugimura; Keio University Hospital, Tsutomu Yoshikawa; Kohsei Chuo General Hospital, Akio Hirai; Kosei General Hospital, Masao Kawaguchi; Kyorin University Hospital, Hideo Yoshino; Mishuku Hospital, Akimi Uehata; Mitsui Memorial Hospital, Kazuhiro Hara; Musashino Red Cross Hospital, Tohru Obayashi; Disaster Medical Center, Yasuhiro Satoh; National Hospital Organization, Tokyo Medical Center, Yukihiko Momiyama; Nihon University Itabashi Hospital, Tadateru Takayama; Nihon University Nerima Hikarigaoka Hospital, Seiji Fukushima; Nippon Medical School Hospital, Keiji Tanaka; Nippon Medical School Tama-Nagayama Hospital, Hirotsugu Atarashi; Nishiarai Hospital, Katsumi Saito; Nishitokyo Central General Hospital, Hiroyuki Suesada; Kanto Medical Center NTT EC, Satoshi Ohnishi; Ome Municipal General Hospital, Shigeo Shimizu; Sakakibara Heart Institute, Tetsuya Sumiyoshi; Senpo Tokyo Takanawa Hospital, Masato Yamamoto; Showa General Hospital, Yuji Kira; Showa University Hospital, Youichi Kobayashi; Social Insurance Central General Hospital, Makoto Noda; St. Luke’s Hospital, Yuji Kira; Showa University Hospital, Nihon University Hospital, Ken Nagao; Tama Nambu Chiiki Hospital, Hiroyuki Takata; Teikyo University Hospital, Takaaki Isshiki; The Cardiovascular Institute, Akira Koike; Tobu Chiiki Hospital, Takashi Tamura; Toho University Omori Medical Center, Nobuya Koyama; Toho University Ohashi Medical Center, Masato Nakamura; Tokai University Hachioji-Hospital, Yoshinori Kobayashi; Tokyo Kosei Nenkin Hospital, Seiji Ayabe; Tokyo Medical and Dental University, Mitsuaki Isobe; Tokyo Medical University Hospital, Akira Yamashina; Tokyo Medical University, Hachioji Medical Center, Hiroshi Kobayashi; Tokyo Metropolitan Bokutoh General Hospital, Ichiro Kubo; Tokyo Metropolitan Fuchu Hospital, Tetsuro Ueda; Tokyo Metropolitan Geriatric Hospital, Kazumasa Harada; Tokyo Metropolitan Hiroo Hospital, Harumizu Sakurada; Tokyo Metropolitan Police Hospital, Tetsuro Shirai; Tokyo Rinkai Hospital, Toru Kono; Saiseikai Central Hospital, Hideo Mitamura; Tokyo Women’s Medical University Hospital, Nobuhisa Hagiwara; Tokyo Women’s Medical University Medical Center East, Kuniaki Otsuka; Toranomon Hospital, Sugao Ishiwata; Tokyo Metropolitan Health and Medical Treatment Corporation, Toshima Hospital, Takashi Shibui; University of Tokyo Hospital, Ryozo Nagai.