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In Japan, the recent status of the mortality of atrial fibrillation (AF) patients is still unclear.
Methods and results
We used a single-hospital based cohort database in an urban city (Tokyo) in Japan, including all the new visitors from 2004 to 2009 (n = 13,228). The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316–318), 16 (95% CI, 16–16), and 238 (95% CI, 237–239), respectively. The age-adjusted relative risk of AF on all-cause mortality was 1.7 in the particular population.
Conclusions
The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve regarding Japanese AF patients.
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
Rapid increase in estimated number of persons with atrial fibrillation in Japan: an analysis from national surveys on cardiovascular diseases in 1980, 1990 and 2000.
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
Rapid increase in estimated number of persons with atrial fibrillation in Japan: an analysis from national surveys on cardiovascular diseases in 1980, 1990 and 2000.
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
NAGOYA HEART Study Group Rationale and design of the NAGOYA HEART Study: comparison between valsartan and amlodipine regarding morbidity and mortality in patients with hypertension and glucose intolerance.
J-RHYTHM Registry Investigators Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation – the J-RHYTHM Registry study design.
Recent trends in the incidence rates of and death rates from atrial fibrillation complicating initial acute myocardial infarction: a community-wide perspective.
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
]. In this situation, we aimed to identify the recent mortality of AF patients in a single hospital-based cohort in an urban city of Japan. Although the population is restricted to a particular setting, the data provide the most recent status regarding the mortality of AF patients in Japan.
Methods
Study patients
The Shinken Database was established comprising all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan (“Shinken” is an abbreviated name in Japanese for the name of the hospital), and excluded patients with active cancer and any foreign travellers. The principle aim of this hospital-based database is a surveillance of the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan [
]. The registry started in June 2004, and thereafter patients have been continually registered to the database annually.
The data in the present study was derived from this database between June 2004 and March 2010 (Shinken Database 2004–2009) including 13,228 new visiting patients (AF was diagnosed in 1942 patients).
Data collection at initial visit
In each patient, after obtaining an electrocardiogram and chest X-ray, the cardiovascular status was evaluated using echocardiography, an exercise test, 24-h Holter recordings, and blood laboratory data within 3 months after the initial visit, according to the decision by the attending physicians. The information regarding medications was obtained from the hospital database within 3 months after the initial visit. Details have been published elsewhere [
The health status and the incidence of cardiovascular events and mortality are maintained in the database by being linked to the medical records of the hospital, and by study documents of prognosis sent once per year to those who stopped hospital visits or who were referred to other hospitals.
In the present data analysis, the follow-up data after April 1st, 2010 were excluded. Therefore, the end of the follow-up period was defined as one of the following three: (1) the date of death, if the date was prior to March 31st, 2010; (2) the final hospital visit or the final response to our study documents of prognosis with the confirmation of being alive prior to March 31st, 2010; and (3) March 31st, 2010, when the date of death, the final hospital visit, or the final response to our study documents of prognosis were later than April 1st, 2010.
Ethics
The ethical committee at the Cardiovascular Institute granted ethical permission for this study and all the patients gave written informed consent.
Definition of AF
In the present study, AF was diagnosed by electrocardiographic recordings, including 12-lead surface electrocardiograms and 24-h Holter recordings within the 3 months after the initial visit, and by the medical history of AF from the referring physicians. New-onset AF later than 3 months after the initial visit was not included in the diagnosis of AF in the present study.
Diagnosis of death
We confirmed deaths of study patients by the medical records of our hospital or by the information obtained from follow-up. Deaths from stroke (both of ischemic and haemorrhagic) and cardiovascular diseases were defined when the causes of death were classified into ICD 10 code numbers of I60-I69 and I00-I99, respectively [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
In the patients’ background, the categorical and consecutive data are presented as number (%) and mean ± standard deviation, respectively. The chi-square test was used for the group comparison, and the unpaired t-test and the one-way analysis of variance were used for the comparison of the consecutive variables between 2 groups and more than 2 groups, respectively. The crude death rates of AF patients were compared with those of non-AF patients, calculating the relative risk and the 95% confidence intervals both in the total population and in the separated age-stratifications.
Thereafter, the age-adjusted death rates of AF patients were calculated using the Japanese standard population model of 1985. Then, age-adjusted relative risks were calculated using the Mantel-Haenszel method adjusted by age categories.
These analyses were performed using SPSS (SPSS Inc., Chicago, IL, USA) for Windows (Microsoft Corp., Redmond, WA, USA), version 14.0 software. Statistical significance was set at two-sided p-value of <0.05.
Results
Characteristics of the study patients
The characteristics of the study patients (AF 1942 and non-AF 11,286) are shown in Table 1. AF patients in the present study included 1426 men (73%) and had a mean age of 66.4 years. Among them, co-existing organic heart diseases, symptomatic heart failure (New York Heart Association ≧II), systolic dysfunction [left ventricular ejection fraction (LVEF) ≦40], hypertension, diabetes mellitus, and history of cerebral infarction or transient ischemic attack (TIA) existed in 666 (34%), 395 (20%), 148 (8%), 853 (43%), 341 (18%), and 123 (6%), respectively. The prescription rates of class I, II, III and IV anti-arrhythmic drugs in AF patients were 27%, 32%, 3%, and 23%, respectively, and digitalis was prescribed in 18%. Warfarin and antiplatelet drugs were prescribed in 46% and 42% of AF patients, respectively. As compared with non-AF (Table 1), age, the prevalence of co-existing organic heart diseases, heart failure, hypertension, diabetes mellitus and the history of cerebral infarction or TIA were significantly higher in AF patients, except for ischemic heart disease.
Table 1Characteristics of study patients with/without atrial fibrillation: Shinken Database 2004–2009, Tokyo, Japan.
The characteristics of the AF patients in age-stratifications by decade are shown in Table 2. The prevalence of co-existing diseases significantly increased as age progresses, while that of cardiomyopathy and systolic dysfunction (LVEF ≦40%) was highest in the stratification of 40–49 years. The prescription rates of anti-arrhythmic drugs also significantly increased according to increment of age, except for class III drugs.
Table 2Characteristics of atrial fibrillation patients by age stratifications: Shinken Database 2004–2009, Tokyo, Japan.
The average follow-up periods of AF and non-AF patients were 775.5 ± 622.8 days and 687.4 ± 612.8 days, respectively. The crude death rates for all-cause, stroke, and cardiovascular death with AF patients were 1091, 97, and 727 per 100,000 patient-years, approximately twice as high as those of non-AF patients (522, 47, and 362 per 100,000 patient-years, respectively).
The crude death rates of AF and non-AF patients in age-stratifications are shown in Fig. 1. The death rates for all-cause, stroke and cardiovascular death with AF patients in separated age-stratifications by decade steadily increased from all 0 in 20–29 years to 2241, 303, and 1664 per 100,000 patient-years in ≧80 years, respectively. Meanwhile, the age-stratified death rates for all-cause, stroke, and cardiovascular death with non-AF patients were at a low level before 69 years and then increased to 2195, 179, and 1523 per 100,000 patients-years in ≧80 years, respectively.
Figure 1Crude death rates in age stratifications of patients with and without atrial fibrillation (AF): Shinken Database 2004–2009. Crude death rates for (a) all-cause, (b) stroke, and (c) cardiovascular death of patients with and without AF are shown in age stratifications.
The relative risks of the death rates between AF and non-AF patients are shown in Table 3. That for all-cause death between AF and non-AF patients was 3.38 (95% CI, 1.13–10.0) in 50–59 years, then gradually decreased with increasing of age to 1.10 (95% CI, 0.63–1.92) in ≧80 years. That for stroke death was 5.08 (95% CI, 0.31–81.2) in 60–69 years, then decreased to 0.99 (95% CI, 0.11–8.85) in 70–79 years, and 1.68 (95% CI, 0.30–9.19) in ≧80 years. That for cardiovascular death was 4.86 (95% CI, 1.31–18.0) in 50–59 years, then gradually decreased to 1.09 (95% CI, 0.55–2.14) in ≧80 years. The relative risks were incomputable under 40–49 years for all-cause death and for cardiovascular death and under 50–59 years for stroke death, because the number of deaths was small either in AF or non-AF patients.
Table 3Relative risks of atrial fibrillation on mortality in age stratifications: Shinken Database 2004–2009, Tokyo, Japan.
Relative risks of atrial fibrillation on mortality [95% CI]
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
Cardiovascular death
4.86 [1.31–18.0]
60–69
All-cause death
2.69 [1.20–6.02]
Stroke death
5.08 [0.31–81.2]
Cardiovascular death
2.11 [0.74–6.00]
70–79
All-cause death
1.68 [0.90–3.13]
Stroke death
0.99 [0.11–8.85]
Cardiovascular death
1.55 [0.71–3.34]
≧80
All-cause death
1.10 [0.63–1.92]
Stroke death
1.68 [0.30–9.19]
Cardiovascular death
1.09 [0.55–2.14]
Total
All-cause death
2.08 [1.47–2.94]
Stroke death
2.06 [0.64–6.56]
Cardiovascular death
2.00 [1.31–3.05]
CI, confidence intervals.
a Relative risks of atrial fibrillation on mortality for any types of death in 20s, 30s, and 40s age-categories and for stroke death in 50s age-category were not calculated, because of the small number of deaths in either of patients with/without atrial fibrillation in the categories.
We calculated the age-adjusted death rates for all-cause, stroke, and cardiovascular death with the AF and the non-AF patients in the present study. The age-adjusted death rates for all-cause, stroke, and cardiovascular death were 317 (95% CI, 316–318), 16 (95% CI, 16–16), and 238 (95% CI, 237–239) per 100,000 patient-years in AF patients and 182 (95% CI, 181–183), 12 (95% CI, 11–12), and 141 (95% CI, 140–141) per 100,000 patient-years in non-AF patients, respectively.
The age-adjusted relative risks of AF of all-cause, stroke, and cardiovascular death were 1.71 (95% CI, 1.20–2.43), 1.61 (95% CI, 0.50–5.16), and 1.64 (95% CI, 1.07–2.52), respectively.
Discussion
Major findings
In the present study, we identified the non-adjusted and age-adjusted death rates of AF and non-AF patients in a cardiovascular hospital in an urban city of Japan. The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316–318), 16 (95% CI, 16–16), and 238 (95% CI, 237–239) per 100,000 patient-years, respectively. The age-adjusted relative risk of AF on the all-cause mortality was 1.7 in this particular population. The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve.
Comparison with previous studies
In previous Western reports, the relative risk of AF on mortality has been identified as approximately 1.5–2 times [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
]. In the present study, the age-adjusted relative risk of AF on mortality was approximately 1.7 times, mostly compatible to the previous reports both in Western countries [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
], 61.5% of AF patients aged 55–74 years died at 10 years of follow-up in men and 57.6% died in women. Moreover, in the population, over 90% of AF patients aged 85–94 years died at 10 years of follow-up, both men and women. In another report from the USA regarding first detected AF [
], the Kaplan-Meier estimate of survival at 4 months was 83% (mortality 17%) and that at 5 years was 52% (mortality 48%). However, in Japan, the report of a nationwide, general population-based cohort (NIPPON DATA 80) [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
] identified that the age-adjusted death rates for all-cause death in AF patients was 2173 per 100,000 patient-years (2.2% per year), much lower than those of the Western reports. Furthermore, in the present study of hospital-based cohort in an urban area of Japan, the age-adjusted death rates for all-cause death in AF patients was 317 per 100,000 patient-years (0.3% per year), further lower than that of NIPPON DATA 80 [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
The lower mortality of AF patients in the present study compared to the previous Western and Japanese reports might be derived from many reasons. First, it would be likely that the difference is derived from the difference of the patients’ backgrounds. Approximately 30–40% of AF patients have ischemic heart disease in Western countries [
Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation.
Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation.
Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation.
] is 1.5 times to twice of that of ours. These differences in patients’ backgrounds might be affected by the variations of lifestyles, health insurance, and hospital access according to countries or to locations, and the difference should lead to the different prognosis.
Second, there seem to be differences derived from the study style between the general population and the hospital-based cohort. Several reports from Western countries [
Recent trends in the incidence rates of and death rates from atrial fibrillation complicating initial acute myocardial infarction: a community-wide perspective.
] have demonstrated that the mortality of AF patients in hospital-based cohorts has been significantly improved, although that in the general population has not [
]. It should be remembered that, in the general population, the majority of mortality events with AF patients occur within 30 days after the initial detection [
]. It suggests that critical patients in this very early phase might be missing in the cardiovascular hospitals like ours. Such inherent selection bias in hospital-based cohorts could result in the difference in mortality compared to the general population.
Third, the difference could be derived also from the difference of the time. It has already been several decades since the previous studies were started [
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
], and there have been numerous changes in the management of cardiovascular diseases, including heart failure, stroke, and coronary artery disease, as well as AF itself. Notably, strongly influenced by the AFFIRM [
Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation.
Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
] and emphasis on the importance of anticoagulation for stroke prevention, the prescription rate of warfarin with AF patients in Japanese cardiovascular hospitals substantially increased from 14% in the 1990s [
Hokkaido Atrial Fibrillation Study Group Prevalence and clinical characteristics of patients with atrial fibrillation: analysis of 20,000 cases in Japan.
]. Considering these changes, it is conceivable that mortality of AF progressively improved in recent decades.
Relative risks of AF in age-stratifications
In the present study, we report that the relative risks of AF on the mortality were inversely related to the increasing of age. Although it seems to be paradoxical, we can notice that it was similarly observed in the data of the Framingham study [
]. The inverse relationship might derive from the characteristics in the background of AF patients, where the prevalence of severe heart failure (with decreased left ventricular function) was relatively high in younger patients (Table 2). Considering that the mortality rates for cardiovascular death, but not for stroke death, in the younger age groups were higher in AF patients than in non-AF patients (Fig. 1), non-stroke cardiovascular death, including severe heart failure with cardiomyopathy, might be the remaining target to improve the mortality of AF in the future.
Clinical implications
Currently, there have been several discussions on what are the main tasks to be solved in the management of AF patients. The discussions have been diverse, from reducing the incidence of mortality, stroke, and hospital admissions to improvement of quality of life. Recently in Japan, several clinical trials have been conducted with AF patients [
Dose–response effects of bepridil in patients with persistent atrial fibrillation monitored with transtelephonic electrocardiograms: a multicenter, randomized, placebo-controlled, double-blind study (J-BAF Study).
]. Although these trials should require the basic information regarding the real-world status of Japanese AF patients, including the mortality, morbidity, and quality of life, such data have been still scarce in Japan.
The present study identified that the mortality of AF patients, at least in a hospital-based cohort of an urban city area, was extremely low. Although the results could not be easily expanded to the nationwide hospitals or to the general population, our results would imply that studies regarding Japanese AF patients should include several combined endpoints other than mortality alone, when they deal with Japanese AF patients in urban areas. Otherwise, when we aim to improve the mortality of Japanese AF patients, we should define a particular population of Japanese AF patients to be adapted to the task, which is linked to particular patients’ backgrounds.
Limitations
The results of the present study have several limitations in the methodologies. First, our database excluded patients with active cancer which strongly influences the all-cause mortality. Actually, in the AFFIRM study [
], cancer-related death represented nearly one-sixth and one-fourth of total mortality in the rate-control and in the rhythm-control arm of AF patients, respectively. Therefore, excluding those with active cancer in the present study, would lead to underestimate the actual mortality rates. Second, because of the indications in consultation for a single-department cardiovascular hospital, it is likely that patients who were firstly diagnosed as having AF with severe stroke or end-stage renal disease were not seen in our database. These high-risk diseases frequently coincide with new-onset AF [
], and such high-risk AF patients are closely associated with increased mortality. Therefore, it should be noted that the AF patients in the present study might be, at least to some extent, limited to those that had survived the risky early phase [
]. Third, the number of events was relatively small in the present study. Therefore, only several events might have changed part of the results.
Conclusions
Our data identified the current status of the mortality of AF patients in a cardiovascular hospital in an urban city of Japan. The current mortality of AF patients in an urban city area was still lower than that in a previous Japanese report, suggesting, at least in part, a recent improvement in mortality with advancement in therapy. However, the results should be interpreted based on the recognition of the possible differences between hospitals and general population and those between urban areas and rural ones. Although limited, it would be noteworthy that the present study provides the most recent data regarding mortality of AF patients in Japan.
References
Benjamin E.J.
Levy D.
Vaziri S.M.
D’Agostino R.B.
Belanger A.J.
Wolf P.A.
Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
Rapid increase in estimated number of persons with atrial fibrillation in Japan: an analysis from national surveys on cardiovascular diseases in 1980, 1990 and 2000.
Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population: nineteen-year follow-up in NIPPON DATA80.
Rationale and design of the NAGOYA HEART Study: comparison between valsartan and amlodipine regarding morbidity and mortality in patients with hypertension and glucose intolerance.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation – the J-RHYTHM Registry study design.
Recent trends in the incidence rates of and death rates from atrial fibrillation complicating initial acute myocardial infarction: a community-wide perspective.
Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation.
Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation.
Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
Dose–response effects of bepridil in patients with persistent atrial fibrillation monitored with transtelephonic electrocardiograms: a multicenter, randomized, placebo-controlled, double-blind study (J-BAF Study).
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