Circ J 2006; 70: 1256–1262

Current Status of the Background of Patients With Coronary Artery Disease in The Japanese Coronary Artery Disease Study (The JCAD Study)

The Japanese Coronary Artery Disease (JCAD) Study Investigators*

Background Although the morbidity and mortality of coronary artery disease (CAD) vary widely with race and lifestyle, Japanese CAD patients have been clinically managed according to the guidelines of Western coun- tries. To draft guidelines specifically for Japanese CAD patients, a database that describes how Japanese CAD patients are currently managed and the outcomes of those managements practices is required. Methods and Results Patients diagnosed as having 75% or higher stenosis according to the American Heart Association classification in at least 1 branch of the coronary arteries by cardiac catheterization were enrolled in the study. Of 15,628 patients screened from April 2000 to March 2001, 13,812 of them met the inclusion criteria and were followed up for a mean period of 2.7 years. The incident rate of events was 62.8 per 1,000 patients-year including all-cause mortality of 17.5 and total cardiac events of 47.4 per 1,000 patients-year which is much higher than previous reports in Japan. The incident rate of acute myocardial infarction in this study cohort was 7.5 events per 1,000 patients-year. Conclusion The database provides a large body of information on Japanese CAD patients who have significant coronary atherosclerosis diagnosed by coronary angiography, which will be useful for planning future random- ized controlled trials. (Circ J 2006; 70: 1256–1262) Key Words: Coronary angiography; Coronary artery disease; Cohort study; Internet registration

he Japanese population dynamic statistics show that style, pharmacokinetics etc of Japanese are different from there were 159,545 deaths from heart disease in Westerners lead to us conducting this study to draft guide- T 2003, consisting 15.7% of all-cause deaths.1 Sever- lines applicable for Japanese. al decades ago Japanese used to be more susceptible to We designed the present study to investigate the risk stroke than cardiac diseases, but there is a now remarkably factors and current status of the medical management of declining trend in the mortality rate of stroke in the Japanese CAD patients and how they are reflected in the Japanese population.2 On the other hand, the incidence of cerebro- and cardiovascular events. To meet this purpose, and mortality from coronary heart disease have increased we selected hospitals across Japan where more than 100 slightly in the past couple of decades3 and the incidence of cases of coronary angiography (CAG) are performed annu- such important risk factors as obesity4 and hyperlipidemia5 ally. As a result, 217 hospitals participated in the study and is increasing. a total of 15,628 patients were registered initially. Thus, the Epidemiological studies have shown that the incidence purpose of the present study (Japanese Coronary Artery and mortality of coronary artery disease (CAD) are higher in Disease Study (JCAD Study)) was to explore the current Western countries than in Asian countries.6 The Framingham status of Japanese CAD patients and clarify the difference Study showed that the risk factors of CAD consist of in CAD outcomes between men and women or among hyperlipidemia, hypertension, smoking and diabetes melli- those who have different numbers of risk factors, so that tus (DM),7 which were incorporated into several clinical new guidelines for Japanese CAD patients can be drafted. guidelines worldwide. Although several epidemiological We are presenting the outline of the JCAD Study database studies on CAD risks have been conducted in Japan, the re- in this paper. Detailed data related to CAD risk factors, sults have not been sufficient to define treatment strategies medical management, and occurrence of cerebro- and car- for Japanese patients, leaving Japanese cardiologists to use diovascular events with various drug treatments will be the Western guidelines for practical reasons. Furthermore, published subsequently. the fact that the mortality of Japanese CAD patients is 20– 30% of Westerners and that the genetic background, life- Methods Patients (Received February 3, 2006; revised manuscript received July 27, The complete protocol of this study with the purpose, 2006; accepted August 3, 2006) *The JCAD Study Investigators are listed in Appendix1. study design, criteria for eligibility and exclusion of pa- Mailing address: Ryozo Nagai, MD, Department of Cardiovascular tients, clinical measures, events and statistical analyses has Medicine, Graduate School of Medicine, University of , 7-3-1 been published elsewhere.8 Briefly, consecutive patients Hongo, Bunkyo-ku, Tokyo 113-8655, Japan undergoing CAG for various reasons and who were diag-

Circulation Journal Vol.70, October 2006 JCAD Study 1257

Table 1 Baseline Characteristics of the Population in the JCAD Cohort Study

Total Male Female Number 13,812 10,626 3,186 Age (years) 65.5±9.8 64.5±9.8 68.7±9.1 Diagnosis at the time of registration AMI (%) 2,955 (21.4) 2,318 (21.8) 637 (20.0) OMI (%) 3,913 (28.3) 3,210 (30.2) 703 (22.1) uAP (%) 2,049 (14.8) 1,501 (14.1) 548 (17.2) sAP (%) 3,926 (28.4) 2,852 (26.8) 1,074 (33.7) Other (%) 969 (7.0) 745 (7.0) 224 (7.0) Risk factors Hyperlipidemia (%) 7,547 (54.6) 5,551 (52.2) 1,996 (62.6) Impaired glucose tolerance (%) 5,570 (40.3) 4,193 (39.5) 1,377 (43.2) Hypertension (%) 7,951 (57.6) 5,899 (55.5) 2,052 (64.4) Obesity (%) 4,538 (32.9) 3,499 (32.9) 1,039 (32.6) Smoking habit (%) 5,437 (39.4) 5,010 (47.1) 427 (13.4) Familial history of CAD (%) 2,281 (16.5) 1,756 (16.5) 525 (16.5)

AMI, acute myocardial infarction; OMI, old myocardial infarction; uAP, unstable angina pectoris; sAP, stable angina pectoris; CAD, coronary srtery disease.

Table 2 Incident Rate of Events Total incident rate Male incident rate Female incident rate Events p value /1,000 patients-year All events including death 62.8 61.5 67.1 0.1083 Death All-cause death 17.5 17.6 16.9 0.6037 Cardiac death 7.6 7.5 8.1 0.6243 Cerebral death 0.9 0.9 0.7 0.4807 Vascular death 0.5 0.6 0.0 0.0241 Other causes 8.5 8.6 8.1 0.6475 Cardiac events 47.4 45.6 53.3 0.0098 Acute myocardial infarction 7.5 7.6 7.1 0.5692 Unstable angina pectoris 22.8 21.5 27.2 0.0035 Resuscitated cardiac arrest 0.4 0.4 0.4 0.7825 Congestive heart failure 10.5 9.9 12.5 0.0427 Bypass graft surgery 4.7 4.8 4.4 0.5833 CPAOA 2.8 2.8 2.7 0.8556 Cerebral events Cerebral infarction or hemorrhage 5.7 5.9 5.2 0.4432 Transient ischemic attack 1.0 1.0 0.9 0.7964 Vascular events Aortic aneurysm rupture 0.5 0.7 0.0 0.0136 Aortic dissection 0.3 0.5 0.0 0.0491

CPAOA, cardiopulmonary arrest on arrival. nosed as having 75% or higher stenosis according to the set up and clinical information of the patients was sent to American Heart Association classification in at least 1 the central computer through a Web-based interface. Data branch of the coronary arteries were primary candidates. were sent to the server at the time of patient registration The reasons for performing CAG included old and acute (baseline characteristics) and every 6 months thereafter for myocardial infarction (MI), stable and unstable angina, 3 years, and when events occurred. chronic heart failure, and clinical demand to perform the procedure. All CAG was performed after written informed Investigations consent was given, except in emergency cases where writ- The data collected included CAD risk factors such as ten consent was not available. The patients were informed, hyperlipidemia, impaired glucose tolerance (IGT) includ- however, even in such cases of the risks and benefits of the ing diabetes mellitus, hypertension, smoking, and drinking, procedure. When follow-up data of more than 6 months and markers such as serum total cholesterol, triglyceride, could be obtained or when a cerebro- and cardiovascular systolic and diastolic blood pressures and left ventricular event occurred, including death, within 6 months of enroll- ejection fraction. Complete information about the data ment, the subjects were included in the final analysis. The collection was reported previously.8 patients were followed up for 3 years. Clinical events to be registered in the database were defined as follows: all-cause deaths including cardiac, cere- Data Registration and Accumulation bral, vascular and other deaths, and cerebral, cardiac and All follow-up data were registered electronically over vascular events. Cerebral events included cerebral hemor- the Web. Detailed methods of data registration have been rhage, cerebral infarction and transient ischemic attack. described previously.8 Briefly, a central database server was Cardiac events consisted of fatal and non-fatal MI, unstable

Circulation Journal Vol.70, October 2006 1258 THE JCAD STUDY INVESTIGATORS

Table 3 Difference in the Incident Rate of Events Between MI and Non-MI Patients Non-MI incident rate MI incident rate Events p value /1,000 patients-year All events including death 62.8 62.8 0.7292 Death All-cause death 14.6 20.4 0.0000 Cardiac death 5.2 10.1 0.0000 Cerebral death 0.9 0.9 0.7185 Vascular death 0.5 0.4 0.5379 Other causes 8.0 9.0 0.2353 Cardiac events 47.1 47.6 0.6443 Acute myocardial infarction 5.7 9.4 0.0000 Unstable angina pectoris 27.5 18.0 0.0000 Resuscitated cardiac arrest 0.3 0.5 0.1865 Congestive heart failure 6.4 14.7 0.0000 Bypass graft surgery 5.9 3.5 0.0008 CPAOA 2.2 3.3 0.0423 Cerebral events Cerebral infarction or hemorrhage 6.4 5.1 0.1265 Transient ischemic attack 1.1 1.0 0.8492 Vascular events Aortic aneurysm rupture 0.7 0.4 0.2217 Aortic dissection 0.5 0.2 0.1747

MI, myocardial infarction. Other abbreviations see in Table2.

Table 4 Causes of Death factors, 54.6% of the patients had hyperlipidemia and 57.6% had hypertension; 40.3% had IGT; and more than Total Male Female 65% had multiple risk factors of lifestyle-related diseases: Acute myocardial infarction 65 47 18 35.9% had 2 risk factors, 23.5% had 3 and 5.9% had 4 risk Other cardiac death 221 168 53 factors. Major vascular death 17 17 0 Cerebral death 33 27 6 Other causes 323 252 71 Incident Rate of Events Total 659 511 148 The incident rates of events as expressed in events per 1,000 patients-year are shown in Table 2. Any events, including all-cause deaths, were 62.8. The incidence for the 6,868 patients diagnosed as having MI at the time of reg- angina, congestive heart failure, coronary bypass graft sur- istration was 62.8, and for non-MI patients (6,944) the gery, resuscitated cardiac arrest and cardiopulmonary arrest annual rate of events was also 62.8. The rate of all-cause on arrival (CPAOA). Angiographical restenosis inciden- deaths was 17.5, of which 9.0 were deaths from cerebro- tally found during routine follow-up CAG without clinical and cardiovascular events and 8.5 were from other causes. symptoms was excluded from events registration. Aortic The rate of cardiac events was 47.4, which was 7.1-fold dissection and rupture of aortic aneurysm were classified as higher than that of cerebral events (6.7) and the rate of vascular events. vascular events was 0.8. There were significant differences between male and female patients for vascular deaths Ethical Considerations (p=0.02), cardiac events (p<0.01), unstable angina pectoris The protocol of this study was approved by the Central (p<0.005), congestive heart failure (p<0.05), aortic aneu- Institutional Review Board of the University of Tokyo. rysm rupture (p=0.01) and aortic dissection (p<0.05). As for informed consent, each attending physician ex- Table3 shows the difference in the incident rate of events plained the study to each candidate patient who gave vol- between those patients who had MI at the time of registra- untary written informed consent prior to enrollment. tion and those who did not. Though the overall event rates The data of each patient was made anonymous so that between the 2 groups of patients were not significantly dif- those who handled the data could not identify the patients. ferent, the event rates of all-cause death (p<0.0001), cardiac death (p<0.0001), acute MI (p<0.0001), unstable angina pectoris (p<0.0001), congestive heart failure (p<0.0001) Results bypass graft surgery (p<0.001) and CPAOA (p<0.05) were Follow-up and Baseline Characteristics of the Patients significantly different. Of the 15,628 recruited individuals, 13,812 satisfied the Table 4 shows the numbers for each cause of death. criteria for eligibility (10,626 males, 3,186 females; Nearly half (49.0%) of the deaths were caused by non- Table 1). The follow-up rate was 83.5% and the mean cerebro- and cardiovascular diseases. follow-up period was 2.7 years. Males were younger than females on average (64.5±9.8 years vs 68.7± 9.1 years: Relationship Between Risk Factors and the Incident Rate of p<0.001). Nearly 50% of the 13,812 CAD patients had Events suffered a MI in the past (28.3%) or at the time of registra- The incident rate of composite endpoints in the patients tion (21.4%). Patients with either stable or unstable angina who had 3 or more risk factors was significantly higher comprised more than 40% of the total. With regard to risk than that in those who have less than 3, even when adjusted

Circulation Journal Vol.70, October 2006 JCAD Study 1259

Fig1. Comparison of cumulative events rate between those who have 3 or more risk factors and less than 3. Hazard ratios (HRs) were determined by age- and sex- adjusted Cox’s proportional hazard regression analysis. CI, confidence interval.

Fig2. Comparison of cumulative events rate between those who have diabetes mellitus and those who do not. Hazard ratios (HRs) were determined by age- and sex- adjusted Cox’s proportional hazard regression analysis. CI, confidence interval. for age and sex (Fig1). However, a linear trend of increase Conventionally, guidelines published in Japan for pre- in the incident rate of composite events was not observed vention of ischemic heart disease have cited the data from with the increase in number of risk factors in this study Western studies, which is unsatisfactory for the Japanese (data not shown). When patients were grouped into those patients because the evidence regarding Japanese CAD who had IGT and those who did not, the incident rate of the patients differs quantitatively and qualitatively. This study composite endpoints was significantly higher in the group was conducted to construct a database of angiographically with IGT, even when adjusted for age and sex (Fig2). diagnosed CAD patients to provide information regarding the occurrence of cerebro- and cardiovascular events and the influence of risk factors and medical treatments. The Discussion collected data illustrates the current management and its An increase in the incidence of obesity,4,9 hyperlipi- outcome in Japanese CAD patients, which will be useful demia5 and IGT among the general Japanese population for planning randomized controlled trials in the future. has raised serious concern regarding the potential risk for The prevalence of hyperlipidemia, IGT and hypertension an increase in the incidence of CAD among Japanese. at the time of registration in this study was approximately However, the number of CAD patients has not increased 55%, 40% and 58%, respectively. A report by the Ministry remarkably in the past couple of decades3 and a recent of Health, Labor and Welfare in Japan in 2002 estimated study reported that the incidence of acute MI in Japan is that the morbidity rates of hyperlipidemia, diabetes and still 25% less than in the United States.10 The reason might hypertension were 17.5%, 12.9% and 30.9%, respectively, be attributed to a possible time lag in the occurrence of the in the general adult Japanese population aged 30 years or actual diseases after exposure to the risk for several dec- older. In the present results, the incident rates were approx- ades. In fact, there are studies reporting that aortic plaque imately double or triple the values in that report, which can in the young Japanese population is as prevalent as in reasonably be attributed to the fact that our study comprised Western youth.11 Other reasons might include a big differ- patients who had definite coronary atherosclerosis. In fact ence between Japanese and Western people in the inci- 91.3% of the patients had at least 1 major risk factors, dence of obesity or the level of individual physical activity. which is compatible with reports from Western countries12

Circulation Journal Vol.70, October 2006 1260 THE JCAD STUDY INVESTIGATORS that despite the general belief that only half of the patients References with CAD have risk factors, more than 80% of CAD 1. Japanese Ministry of Health, Labour and Welfare. Vital Statistics of patients actually have 1 or more classic risk factors. Japan, 2003. Tokyo: the Ministry; 2003. The incident rate of CAD is known to differ among 2. Japanese Ministry of Health, Labour and Welfare. Gross Statistics of different population groups. To date, Asians, including Cerebro-cardiovascular Mortality: Vital Statistics Special Report. Tokyo: The Ministry; 2005. Japanese, have been shown to have lower incident rate of 3. Kubo M, Kiyohara Y, Kato I, Tanizaki Y, Arima H, Tanaka K, et al. 6 CAD in the general population compared with Westerners. Trends in the incidence, mortality, and survival rate of cardiovascu- Recent reports have shown that the incident rate of MI in lar disease in a Japanese community: The Hisayama study. Stroke the general Japanese population is in the range of 0.524– 2003; 34: 2349–2354. 10,13 4. Yoshiike N, Seino F, Tajima S, Arai Y, Kawano M, Furuhata T, et al. 1.25 per 1,000 patients-year, which is considerably Twenty-year changes in the prevalence of overweight in Japanese lower than reported in a study conducted in Sweden (3.81– adults: The National Nutrition Survey 1976–95. Obes Rev 2002; 3: 8.81 per 1,000 patients-year), even though the incident rate 183–190. had been declining for 8 years in that region.14 5. Adachi H, Hino A, Imaizumi T. Prediction of cardiovascular mor- The incident rate of MI in this study was 6.77 per 1,000 bidity and mortality based on changes of cholesterol levels in Japan. Cardioangiology 2005; 57: 15–20. patients-year, which is considerably higher than the num- 6. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas bers in the general population or in the primary prevention AM, Pajak A. Myocardial infarction and coronary deaths in the cohort of Japanese with hyperlipidemia treated with sim- World Health Organization MONICA Project: Registration proce- vastatin in the J-LIT study, which was 0.86 per 1,000 dures, event rates, and case-fatality rates in 38 populations from 21 15 countries in four continents. Circulation 1994; 90: 583–612. patients-year. This difference in the rate is reasonably 7. Castelli WP. Epidemiology of coronary heart disease: The Framingham attributed to the fact that participants in the present study study. Am J Med 1984; 76: 4–12. were confirmed to have significant coronary atherosclero- 8. Hayashi D, Yamazaki T. Design and rationale of the Japanese Coro- sis. nary Artery Disease (JCAD) Study: A large-scale, multicentered pro- spective cohort study. Jpn Heart J 2004; 45: 895–911. When the subjects were divided into those who had 2 or 9. Washio M, Hayashi R. Past history of obesity (overweight by WHO less risk factors and those with 3 or more risk factors, a sig- criteria) is associated with an increased risk of nonfatal acute myo- nificant increase in the incidence of composite events was cardial infarction: A case-control study in Japan. Circ J 2004; 68: observed (Fig 1), which concords with results reported 41–46. previously, although the absolute increase in the incident 10. Nishigaki K, Yamazaki T, Fukunishi M, Tanihata S, Fujiwara H. 15 Assessment of acute myocardial infarction in Japan by the Japanese rate was not as high as reported previously. This might be Coronary Intervention Study (JCIS) Group. Circ J 2004; 68: 515– because each of the present subjects already had significant 519. coronary atherosclerosis confirmed by CAG, which on the 11. Imakita M, Yutani C, Sakurai I, Sumiyoshi A, Watanabe T, one hand might have masked the effects of the risk factors Mitsumata M, et al. The second nationwide study of atherosclerosis in infants, children, and young adults in Japan: Comparison with the and might have resulted in more rigorous managements of first study carried out 13 years ago. Ann NY Acad Sci 2000; 902: patients on the other. As shown in Fig2, the incident rate of 364–368. events was significantly higher in patients with IGT than in 12. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, et those without IGT, indicating that IGT is an important risk al. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA 2003; 290: 898–904. factor even when patients are under rigorous medical man- 13. Kodama K, Sasaki H, Shimizu Y. Trend of coronary heart disease and agement. its relationship to risk factors in a Japanese population: A 26-year In conclusion, we have collected a significant amount of follow-up, Hiroshima/Nagasaki study. Jpn Circ J 1990; 54: 414– data concerning Japanese CAD patients, providing enough 421. 14. Rosen M, Alfredsson L, Hammar N, Kahan T, Spetz CL, Ysberg AS. evidence on which guidelines for Japanese CAD patients Attack rate, mortality and case fatality for acute myocardial infarc- can be based. This is one of the largest cohort studies tion in Sweden during 1987–95: Results from the national AMI conducted to date, in which the diagnosis of CAD was register in Sweden. J Intern Med 2000; 248: 159–164. confirmed by CAG in more than 13,000 patients. More 15. Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa analyses of the data obtained should provide more detailed S, et al. Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvas- information regarding Japanese CAD patients. tatin therapy in Japanese patients with hypercholesterolemia. Circ J 2002; 66: 1087–1095. Study Limitations This study is quite unique in the enrolment of a large Appendix 1 number of patients with angiographically-confirmed coro- JCAD Study Investigators nary atherosclerosis. To the best of our knowledge, there Executive Committee Members: Ryozo Nagai (Chair), Tsutomu Yamazaki have not been similar studies of this magnitude conducted (Graduate School of Medicine, University of Tokyo), Akira Kitabatake before in Japan. Because the patients in this study had (Hokkaido University Graduate School of Medicine), Kazuaki Shimamoto unique characteristics, the ability to compare this study (Sapporo Medical University), Kenjiro Kikuchi (Asahikawa Medical College), Ken Okumura (Hirosaki University School of Medicine), Kunio with other controlled studies or studies conducted in the Shirato (Tohoku University Graduate School of Medicine), Yukio general population may be limited. Although we attempted Maruyama (Fukushima Medical University), Masahiko Kurabayashi to match the background data of patients when making (Gunma University Graduate School of Medicine), Kazuyuki Shimada comparisons, there might be situations where those com- (Jichi Medical School), Hiroaki Matsuoka (Dokkyo University School of parisons do not seem entirely appropriate. Medicine), Iwao Yamaguchi (Institute of Clinical Medicine, University of Tsukuba), Shigeyuki Nishimura, Nobuyuki Komiyama (Saitama Medical School), Issei Komuro (Chiba University Graduate School of Medicine), Acknowledgments Katsuo Kanmatsuse (Nihon University Surugadai Hospital), Tamio We thank Mr Genta Miyama and Mr Hiroki Sato for their cooperation Teramoto (Teikyo University School of Medicine), Teruo Takano during this study. (Nippon Medical School), Hiroshi Yamaguchi (Machida Municipal This work was supported by a grant from the Japanese Circulation Hospital), Satoshi Ogawa (Keio University School of Medicine), Seibu Foundation. Mochizuki (The Jikei University School of Medicine), Tetsu Yamaguchi, Shin-ichi Momomura (Toranomon Hospital), Tsutomu Tamura (Itabashi Chuo Medical Center), Nobuharu Akatsuka (International Medical Center

Circulation Journal Vol.70, October 2006 JCAD Study 1261 of Japan), Satoshi Umemura (Yokohama City University School of Inoue, Toshiya Iwasaki, Shunichi Toshima (Kitakanto Cardiovascular Hos- Medicine), Tohru Izumi (Kitasato University School of Medicine), Uichi pital), Hideyuki Fujikawa, Yoshihiro Saito, Kenichi Kimura (Utsunomiya Ikeda (Shinshu University School of Medicine), Yoshifusa Aizawa Social Insurance Hospital), Shigeo Horinaka (Dokkyo University School (Niigata University Graduate School of Medical and Dental Sciences), of Medicine), Masafumi Onoda, Masanori Takada, Akira Machiyama Hiroshi Mabuchi (Graduate School of Medical Science, Kanazawa (Moka Hospital), Akira Komaba (Kamitsuga General Hospital), Hiroshi University), Noboru Takekoshi (Kanazawa Medical University), Takayuki Yagi, Noriaki Tuchiya, Yosuke Mori (Ohtawara Red Cross Hospital), Itoh (Aichi Medical University), Haruo Hirayama (Nagoya Daini Red Hitoshi Yokozuka (Ashikaga Red Cross Hospital), Takaaki Katsuki, Cross Hospital), Takahiko Suzuki (Toyohashi Heart Center), Hisayoshi Osamu Mizuno (Jichi Medical School), Keiji Iida, Tsuyoshi Enomoto, Fujiwara (Gifu University Graduate School of Medicine), Takeshi Bunpei Niho, Shoji Suzuki, Takuji Tomizawa (Tsukuba Memorial Hospi- Nakano (Mie University School of Medicine), Shigetake Sasayama tal), Shigeyuki Watanabe, Yoshihiro Seo (Institute of Clinical Medicine, (Hamamatsu Rosai Hospital), Masatoshi Fujita (Faculty of Medicine, University of Tsukuba), Hiroshi Maeda (Ibaraki Seinan Medical Center), Kyoto University), Hiroshi Kamihata (Kansai Medical University), Shojiro Ishibashi (Ibaraki Prefectural Central Hospital), Minoru Murata Masatsugu Hori ( University Graduate School of Medicine), (Mito-Saiseikai General Hospital), Muneyasu Saito, Norifumi Kubo Hirofumi Kambara (Shizuoka General Hospital), Ichiro Nishio (Wakayama (Omiya Medical Center, Jichi Medical School), Shigenori Morooka, Medical University), Mitsuhiro Yokoyama ( University Graduate Hirotoshi Kamishirado (Koshigaya Hospital, Dokkyo University School School of Medicine), Chiaki Shigemasa (Tottori University, Faculty of of Medicine), Osami Kohmoto, Takashi Serizawa (Saitama Medical Medicine), Tohru Ohe (Okayama University Graduate School of Medi- School), Nobuo Yoshimoto, Syugo Tanaka, Yoshiaki Maruyama (Saitama cine and Dentistry), Kazuaki Mitsudo (Kurashiki Central Hospital), Medical Center), Masahiro Suzuki (National Saitama Hospital), Fumitaka Masunori Matsuzaki (Yamaguchi University School of Medicine), Jitsuo Ohsuzu, Toshio Shibuya (National Defense Medical College), Yoshio Higaki (Ehime University School of Medicine), Kenji Sunagawa (Kyusyu Kobayashi, Yoshiaki Masuda (Chiba University Graduate School of Medi- University Graduate School of Medical Sciences), Tsutomu Imaizumi cine), Kyoichi Mizuno, Shunta Sakai, Fumiyuki Ishibashi, Shigenobu (Kurume University School of Medicine), Katsusuke Yano (Course of Inami, Masamichi Takano (Chiba-hokusoh Hospital, Nippon Medical Medical and Dental Sciences, Graduate School of Biomedical Sciences, School), Mitsuyuki Shimizu, Masafumi Kusaka (Kashiwa Hospital, The Nagasaki University), Hisao Ogawa (Graduate School of Medical Sci- Jikei University School of Medicine), Tatsuji Kanoh, Shigeru Matsuda ences, Kumamoto University), Chuwa Tei (Kagoshima University). (Juntendo University Urayasu Hospital), Hidefumi Ohsawa (Sakura Hos- Consultants: Yoshio Yazaki (National Hospital Organization), Akira pital, Toho University School of Medicine), Toshiharu Himi (Kimitsul Yamamoto (National Cardiovascular Center Research Institute). Central Hospital), Kazuhiro Hara (Mitsui Memorial Hospital), Ikuyoshi Data Management and Statistics: Tsutomu Yamazaki, Dobun Hayashi, Watanabe, Hirofumi Kawamata (Nihon University Surugadai Hospital), Hiroshi Nishimura, Takahide Kohro (Graduate School of Medicine, Satoru Yoshida (The Jikei University School of Medicine), Sugao University of Tokyo). Ishiwata, Yo Fujimoto (Toranomon Hospital), Tadanori Aizawa, Ken Members Ogasawara (Cardiovascular Institute Hospital), Toshiyuki Degawa Hokkaido: Takashi Takenaka (Hokkaido Cancer Center), Hiroshi Oimatsu, (Senpo-Tokyo Takanawa Hospital), Hiroyuki Daida (Juntendo University Akita Endo, Hiroyuki Kita, Hisataka Sasao (Hakodate Goryokaku School of Medicine), Akihiro Nakagomi, Yoshiki Kusama, Hoshi Takano, Hospital), Teisuke Anzai (NHO Hakodate National Hospital), Takayuki Satoshi Aoki (Nippon Medical School), Dobun Hayashi, Hiroshi Matsuki (Shin-Nittetsu Muroran General Hospital, Muroran), Tetsuro Nishimura, Takahide Kohro (Graduate School of Medicine, University of Shoji, Takeo Adachi, Masatada Fukuoka (Muroran City General Hospi- Tokyo), Keichoh Miyamoto, Yojiro Sukoh, Takashi Tamura, Rei tal), Takashi Shogase (Nikko Memorial Hospital), Noriyoshi Kato Hasegawa (Tobu Chiiki Hospital), Shingo Seki, Kiyoshi Kanae, Tohru (Sapporo City General Hospital), Masahiro Tsuzuki, Hiroshi Kobayashi Arino (Aoto Hospital, The Jikei University School of Medicine), Masahiko (Sapporo Cardiology Clinic), Kazufumi Tsuchihashi (Sapporo Medical Harada, Seiichiro Taguchi, Toshiyuki Asahara, Mitsuhiro Tohma, Masato University), Kazushi Urasawa, Tetsuro Koya, Hiroyuki Tsutsui (Hokkaido Yamamoto (Tokyo Rosai Hospital), Kenji Wagatsuma (Toho University University Graduate School of Medicine), Naoki Funayama (Hokkaido Omori Medical Center), Teruhiko Aoyagi (Japanese Red Cross Medical Cardiovascular Hospital), Yutaka Yamada, Yasumi Igarashi, Kunihiko Center), Yoshiyuki Haneda, Toshiyuki Takahashi, Kazuro Sugishita (JR Tateda (Asahikawa City Hosipital), Yoshinao Ishii, Kunihiko Tateda Tokyo General Hospital), Masato Nakamura (Toho University Ohashi (Asahikawa City Hosipital), Junichi Katoh (Asahikawa Kousei Hosipital), Medical Center), Akira Yamashina, Nobuhiro Tanakak, Shigeki Itoh, Naoyuki Hasebe (Asahikawa Medical College). Naohisa Shido (Tokyo Medical University), Yasushi Asakura (Keio Tohoku and Koshinetsu: Yasuhiro Fujino (Aomori Prefectural Central University School of Medicine), Satoshi Saito, Masafumi Akabane, Hospital), Fumitaka Kikuchi (Hachinohe City Hospital), Hiroyuki Hanada Tadateru Takayama, Makoto Ichikawa (Nihon University School of (Hirosaki University School of Medicine), Kenji Tamaki (Iwate Prefec- Medicine), Takaaki Isshiki, Masahiko Ochiai (Teikyo University School tural Central Hospital), Akihisa Fujino (Yonezawa City Hospital), Yutaka of Medicine), Toshiro Minami, Kouichi Hashimoto, Satoshi Imamoto, Igarashi (Tsuruoka City Syonai Hospital), Tetsuya Hiramoto, Shigenori Shinichiro Ishikawa (Machida Municipal Hospital), Masayuki Taniguchi, Kitaoka, Kanichi Inoue (Sendai Medical Center), Masaharu Kanazawa Ikuo Taniguchi (Daisan Hospital, The Jikei University School of Medi- (Sendai Open Hospital), Tsukasa Asakura (Ohara Medical Center), Minoru cine), Hirotsugu Atarashi, Chikao Ibuki, Koichi Nagasawa, Hiroshi Mitsugi, Kazuhira Maehara (Fukushima Medical University), Shigebumi Kishida (Nippon Medical School, Tama-Nagayama Hospital), Kazuo Suzuki (Fukushima Rosai Hospital), Tomiyoshi Saito, Tsuneyoshi Saito Munakata, Takahiro Uchida (Nippon Medical School, Second Hospital), (Shirakawa Kosei General Hospital), Kenji Owada, Akira Hirosaka, Jun Kenichi Kato, Kazuhiko Yumoto (Yokohama Rosai Hospital), Youichi Kobayashi, Yoshiyuki Kamiyama, Hironori Uekita (Ohta Nishinouchi Takeyama, Fuyuki Asano, Yutaka Shimizu (Showa University Fujigaoka Hospital), Takaaki Kubo (Takeda General Hospital), Toshikatsu Ichihara, Hospital), Toshiro Kurosawa (Kitasato University School of Medicine), Nobuo Komatsu (Iwaki Kyoritsu General Hospital), Izumi Miyazawa, Kazuo Kimura, Tomoaki Shimizu (Yokohama City University Medical Shoji Sawaki (Nagano Red Cross Hospital), Hiroyuki Ichinose (Shinonoi Center), Tsutomu Endo, Yuzuru Yoshii (Saiseikai Yokohama City Nanbu General Hospital), Keishi Kubo, Hiroshi Tsutsui, Shinichiro Uchikawa Hospital), Kazuaki Uchino, Naomitsu Kuji, Teruyasu Sugano, Kiyoshi (Shinshu University School of Medicine), Tsuneo Nagai (Nagaoka Red Hibi (Yokohama City University School of Medicine), Shinichi Tohyama Cross Hospital), Masaaki Okabe (Tachikawa General Hospital), Fumiaki (Kanagawa Cardiovascular and Respiratory Center), Masato Sawano, Masani (Niigata Prefectural Central Hospital), Takashi Tsuda, Toshio Osamu Yamanaka (International Goodwill Hospital), Ichiro Michishita, Yamaguchi (Kido Hospital), Yusuke Tamura (Saiseikai Niigata Daini Ichiro Mizuguchi (Yokohama Sakae Kyosai Hospital), Takashi Matsubara, Hospital), Hideaki Otsuka, Yasushi Miyakita, Kotaro Higuchi (Niigata Takashi Sakai (Hiratsuka City Hospital), Jiro Yoshioka, Kobari Hospital), Yuuichi Nakamura, Taku Matsubara, Tomoyuki Hori Tokai and Kinki: Akinori Takizawa, Tomoya Onodera (Shizuoka City (Niigata University Graduate School of Medical and Dental Sciences), Shizuoka Hospital), Osamu Doi, Satoshi Kaburagi (Shizuoka General Kaoru Suzuki, Eiichi Itoh (Niigata Prefectural Shibata Hospital), Seiichi Hospital), Sadao Takeda (Shimizu Kosei Hospital), Chiei Takanaka Miyajima (Tsubame Rosai Hospital), Yutaka Nitta (Toyama Red Cross (Hamamatsu Medical Center), Yasuhiro Morita (Hamamatsu Rosai Hospital), Masanobu Namura (Kanazawa Cardiovascular Hospital), Hospital), Toshihiko Nagano (Gifu National Hospital), Sachiro Watanabe, Honin Kanaya, Bunji Kaku (Ishikawa Prefectural Central Hospital), Seiyu Tetsuo Matsubara, Hitoshi Matsuo (Gifu Prefectural Hospital), Hisato Kanemitsu (Kanazawa Medical University), Sumio Mizuno, Kazuo Ohsato Takatsu, Katsumi Ueno, Noriyasu Mori (Gifu Municipal Hospital), (Fukui Cardiovascular Center), Susumu Fujino, Takashi Saga (Fukui Kazuhiko Nishigaki (Gifu University Graduate School of Medicine), Prefectural Hospital), Jong-dae Lee, Hiromasa Shimizu, Hiroyasu Uzui, Norihiko Morita (Matsunami General Hospital), Takahito Sone (Ogaki Akira Nakano (University of Fukui). Municipal Hospital), Hidetoshi Sato (Toyohashi Heart Center), Hirofumi Kanto: Norio Kanazawa, Tetsuro Imanari, Izuru Ochiai (Takasaki National Kanda, Hiroki Kataoka, Hitoshi Ishihara, Toshikazu Tanaka (Okazaki Hospital), Shigeru Oshima, Hiroshi Hoshizaki (Gunma Prefectural Car- City Hospital), Miyoshi Ohno, Haruo Kamiya (Japanese Red Cross diovascular Center), Takesatoru Fukuda (Saiseikai Maebashi Hospital), Nagoya First Hospital), Kenji Okumura (Nagoya University Graduate Akira Hasegawa (Gunma University Graduate School of Medicine), School of Medicine), Mamoru Nanasato (Nagoya Daini Red Cross Nobuyuki Kobayashi (Ota General Hospital), Shuichi Ichikawa, Masahiro Hospital), Yukio Ozaki, Tatsuya Yasukawa, Masato Maekawa (Aichi

Circulation Journal Vol.70, October 2006 1262 THE JCAD STUDY INVESTIGATORS

Medical University), Taizo Kondo, Yoshifumi Awaji (Komaki City Hos- (Okayama University Graduate School of Medicine and Dentistry), pital), Kazuyoshi Sakai (Tosei General Hospital), Mitsuhiro Okamoto, Kazushige Kadota (Kurashiki Central Hospital), Nobuo Shiode (Matsue Toyoaki Matsushita (Aichi Prefectural Owari Hospital, Cardiovascular Red Cross Hospital), Tsuyoshi Oda, Yasuaki Wada (Shimane Prefectural Center), Tokuji Konishi, Takashi Yada (Mie Prefectural General Medical Central Hospital), Shunichi Kaseda (Hiroshima Red Cross Hospital & Center), Satoshi Ichimiya, Masaaki Kanashiro (Yokkaichi Municipal Atomic-bomb Survivors Hospital), Seiichi Haruta (Fukuyama Cardiovas- Hospital), Masayuki Hamada, Masatoshi Miyahara (Suzuka Central cular Hospital), Yasuhiko Hayashi (Tsuchiya General Hospital), Hiroshi General Hospital), Tsutomu Okinaka (Mie University School of Medi- Ogawa, Takatoshi Wakeyama (Tokuyama Central Hospital), Shiro Ono, cine), Norimoto Houda, Toshikazu Aoki (Saiseikai Matsuzakal General Kotaro Shiomi (Saiseikai Yamaguchi General Hospital), Kohei Muramatsu Hospital), Takakazu Kohji, Katsutoshi Makino (Matsuzaka Central (Yamaguchi Red Cross Hospital), Takashi Fujii (Yamaguchi University General Hospital), Hideo Nishikawa, Atsushi Nishiyama (Yamada Red School of Medicine), Toshiaki Ashihara, Takashi Nanba, Takaya Cross Hospital), Tetsu Yamakado, Shinya Okamoto (Nabari City Hospi- Fukuyama ( Red Cross Hospital), Takafumi Okura, Yuji Hara tal), Kinzo Ueda, Shin Mizoguchi, Shun-ichi Tamaki, Kazuki Itoh (Ehime University School of Medicine), Yuji Shigematsu (Faculty, (Takeda Hospital), Tetsuo Hashimoto (Takeda General Hospital), Yutaka Nursing and Health Sciences, Ehime University School of Medicine), Furukawa, Hideo Ohtani, Yukihito Sato, Takeshi Kimura, Toru Kita Hiroshi Matsuoka, Hideo Kawakami, Kazuhisa Nishimura (Ehime (Kyoto University), Hiroaki Matsubara (Kyoto Prefectural University Prefectural Imabari Hospital), Takumi Sumimoto (Kitaishikai Hospital), School of Medicine), Ryozo Tatami, Tsuyoshi Takamatsu, Masaru Inoue, Kohji Takahashi (Yawatahama City General Hospital), Takashi Tsuruoka Akira Izawa (Maizuru Kyosai Hospital), Hiroshi Sato (Osaka University (Ehime Prefectural Minamiuwa Hospital), Mareomi Hamada (Uwajima Graduate School of Medicine), Ryuji Nohara (Kitano Hospital), Masaru City Hospital), Yusuke Yamamoto, Masanori Okabe, Koji Todaka, Yutaka Tanaka (Osaka Red Cross Hospital), Akira Ezumi, Hideaki Kataiwa, Akatuka (Saiseikai Fukuoka General Hospital), Yuji Maruoka, Hiroshi Yukichi Abe (Osaka Railway Hospital), Junichi Yoshikawa, Kenei Ando, Yuuko Funakoshi (Hamanomachi Hospital), Takahiro Matsumoto, Shimada (Osaka City University School of Medicine), Takeshi Aoyama, Shigeki Sako, Samon Koyanagi (National Kyusyu Medical Center), Hideo Katsuhisa Ishii, Kunihisa Miwa (Kansai Electric Power Hospital), Tatsuya Tada, Masahiro Mohri, Hiroaki Shimokawa, Akira Takeshita (Kyusyu Sasaki, Osamu Akutagawa, Masaharu Ohmori, Masaki Yamato (Osaka University Graduate School of Medical Sciences), Tetsuji Inou, Michiko Koseinenkin Hospital), Yasuo Sudani (Kansai Medical University), Tanaka (Fukuoka Red Cross Hospital), Hideki Shimomura, Kunihiro Nobuyuki Tsuda, Hisato Nakamori (Kansai Medical University Kori Matsuo, Osamu Hirashima (Fukuoka Tokusyukai Hospital), Shuichi Hospital), Masayoshi Mishima (Kawachi General Hospital), Kazuyoshi Okamatsu, Akira Yamada (Iizukai Hospital), Yousuke Katsuda, Tomoki Hirota (Fuchu Hospital), Mitsuo Matsuda, Takashi Uegaito (Kishiwada Honma (Kurume University School of Medicine), Kunihiko Yamamoto, City Hospital), Hajime Kotoura, Hideaki Hamada (Japanese Red Cross Yoji Hirakawa (St. Mary’s Hospital), Shin Suzuki (Nagasaki Municipal Society, Wakayama Medical Center), Yasushi Hayashi, Masanori Hospital), Yoshihiro Iwasaki (Kohseikai Hospital), Genji Toda (Graduate Hamada (Wakayama Medical University), Yoshio Kusuyama (Wakayama School of Biomedical Sciences, Nagasaki University), Hideki Mori, National Hospital), Tadao Yamamoto, Teruhito Azuma (Kinan General Minoru Hazama (Japanese Red Cross Nagasaki Genbaku Hospital), Hospital), Junya Shite, Katsuya Hata, Hideyuki Takaoka (Kobe Univer- Kazuteru Fujimoto, Hiroo Miyagi (National Hospital Organization sity Graduate School of Medicine), Susumu Sakamoto, Akira Takarada Kumamoto Medical Center), Seigo Sugiyama, Hirofumi Yasue, Kiyotaka (Hyogo Prefectural Awaji Hospital), Yoshiki Takatsu (Hyogo Prefectural Kugiyama (Graduate School of Medical Sciences, Kumamoto Universi- Amagasaki Hospital), Masato Baden (Takarazuka Hospital), Teishi ty), Takashi Honda, Koichi Nakao (Saiseikai Kumamoto Hospital), Kajiya, Shinichiro Yamada, Takatoshi Hayashi (Hyogo Brain and Heart Hiroyuki Torii (Kagoshima City Ishikai Hospital), Syuichi Hamazaki Center), Kojiro Awano (Miki City Hospital). (Kagoshima University), Hitoshi Toda, Hachiro Obata, Souki Lee, Midori Chugoku, and Kyushu: Yasuyuki Yoshida, Hiroshi Nasu, Akihiro Okamura (Kagoshima City Hospital), Tatsuru Matsuoka, Hitoshi Endo, Masahiko Sakamoto, Hisato Moritani (Tottori Prefectural Central Nakashima, Manabu Setoguchi, Masahiro Kameko (National Hospital Hospital), Jiro Miyamoto (Tottori Red Cross Hospital), Ichiro Hisatome, Organization Kyushu Cardiovascular Center). Yoshiaki Inoue (Tottori University, Faculty of Medicine), Satoshi Nagase

Circulation Journal Vol.70, October 2006