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Cause of Death and Associated Factors in Elderly Patients With Atrial Fibrillation　― Long-Term Retrospective Study ―

Background: Oral anticoagulant (OAC) therapy reduces the risk of stroke in patients with atrial fibrillation (AF). This study elucidated the causes of death and related factors in elderly Japanese AF patients. Methods and Results: Over a median (interquartile range [IQR]) follow-up period of 46 (20–76) months, there were 171 all-cause deaths (28% cardiovascular, 46% non-cardiovascular, and 26% unknown causes) among 389 AF patients (median [IQR] age 80 [74–85] years; CHAD2DS2-VASc score 5 [4–6]). Cox regression analysis indicated that diabetes was associated with an increase in all-cause death (hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.02–2.13), whereas hypercholesterolemia (HR 0.53; 95% CI 0.35–0.79), pre-existing heart failure (HR 0.67; 95% CI 0.48–0.95), and OAC use (HR 0.62; 95% CI 0.44–0.88) were associated with reductions in all-cause death. Pre-existing heart failure was associated with both cardiovascular (HR 3.03; 95% CI 1.33–8.20) and non-cardiovascular (HR 0.44; 95% CI 0.30–0.65) deaths, in opposite directions. OAC use was associated with a reduction in cardiovascular death (HR 0.34, 95% CI 0.17–0.69). The predominance of non-cardiovascular death and death-related factors were equivalent regardless of when observations started (before 2009 or in 2009 and later). Conclusions: The predominant cause of death in elderly Japanese AF patients was non-cardiovascular. Distinct clinical factors were associated with cardiovascular and non-cardiovascular death.


Cause of Death in Elderly AF Patients
did not allow the investigators to appropriately identify the cause of death). CV deaths included those resulting from coronary artery disease, cerebral infarction, cerebral hemorrhage, subdural hematoma, aortic dissection, systemic embolism, constrictive pericarditis, congestive heart failure, aortic aneurysm rupture, pulmonary embolism, arterial sclerosis obliterans, and sudden death. Sudden death was defined as an unexpected sudden death from onset to death within 24 h. Non-CV deaths included those resulting from malignant neoplasm, pneumonia, other infectious diseases, ileus, gastrointestinal perforation, renal failure, choking, sarcoidosis, and senility. Senility was defined as the absence of any other fatal disease despite recovery from the underlying disease. Two cardiologists reviewed each medical record to confirm the diagnosis.

Statistical Analysis
The clinical characteristics of the study population according to survival at the end of follow-up period were compared using a t-test or Wilcoxon signed-rank test for continuous variables depending on whether the data were normally distributed, and the Chi-squared test for categorical variables. The normality of distribution was evaluated using the Kolmogorov-Smirnov test. Continuous data are presented as the median with interquartile range (IQR), whereas categorical data are presented as frequencies. The cumulative incidence of clinical outcomes was estimated by the Kaplan-Meier method, and the significance of differences was assessed with the log-rank test.
A multivariate Cox regression model was used on potential confounders to identify factors associated with all-cause death, CV death, and non-CV death. The covariates included age (per 10 years), male sex (vs. female sex), hypertension, diabetes, hypercholesterolemia, coronary artery disease, stroke, heart failure, PAD, sustained AF (vs. paroxysmal AF), and the use of OACs at baseline. To assess death-related factors in the later years of life, a separate Cox analysis was performed for individuals aged ≥75 years. In addition, considering the significant changes in AF therapeutic strategies after the launch of the Guidelines for the Pharmacotherapy of Atrial Fibrillation cases of AF were included in the present study. In the case of patients without ECG records, patients were considered to have AF if the attending physician diagnosed and treated them for AF. Patients <65 years of age were excluded from the study. All data, including comorbidities, drug use, and patient prognosis, were evaluated by reviewing the hospital EMR for each patient (Figure 1).

Definition of Clinical Diseases
Comorbidities diagnosed clinically according to the following criteria were taken into account. Patients were diagnosed with hypertension if they were documented to have a blood pressure of at least 140/90 mmHg or were already on antihypertensive therapy. 13 Diabetes was defined as fasting plasma glucose levels of 126 mg/dL (7 mmol/L), HbA1c of 6.5%, and/or patients clinically identified and treated as having diabetes. 14 Hypercholesterolemia was defined as low-density lipoprotein cholesterol ≥140 mg/dL (5.69 mmol/L) 15 or statin use. Patients with coronary artery disease were defined as those who had significant coronary lesions within the major coronary tree or a history of myocardial infarction (MI), percutaneous coronary intervention, or coronary artery bypass graft. Stroke was defined as a history of brain thromboembolism or bleeding. Peripheral artery disease (PAD) was defined as an anklebrachial index <0.9, 16 or a history of percutaneous transluminal angioplasty or bypass graft. Heart failure was defined as a history of admission for congestive heart failure Stroke risk was assessed using the CHA2DS2-VASc score (

Study Endpoint
The primary endpoint in the analysis was all-cause death and its specific cause(s) during the follow-up period. Causes of death were adjudicated after consideration of all available information and were classified as either CV, non-CV, or undetermined (when the quality of information

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Results
In all, 389 patients who were retrospectively enrolled from 1997 to 2016 were followed for a median duration of 46 months (IQR 20-76 months). The baseline characteristics of the patients stratified according to prognosis are presented in Table 1. The median age of the patients was 77 years (IQR 68-84 years), 54% were men, and the median CH2DS2-VASc score was 5 (IQR 4-6). Hypertension (78%) was the most prevalent comorbidity, followed by heart failure (64%), stroke (45%), hypercholesterolemia (32%), diabetes (32%), and coronary artery disease (23%). Of the (JCS2008), 17 the prognosis of patients in the study was assessed by categorizing them into 2 groups according to when observations began (i.e., before 2009 or in 2009 and later). Statistical analyses were performed using JMP 9.0.2 (SAS Institute, Cary, NC, USA). All statistical tests were 2-sided, and P<0.05 was considered statistically significant.
This study was conducted following the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Social Medical Corporation Yuaikai, Okinawa, Japan (H30R009).  (Table 3A). Characteristic findings of this study were that pre-existing heart failure was associated with poor CV mortality ( Figure 3B), but with better non-CV mortality (Figure 3C). Diabetes was associated with higher CV and non-CV mortality, but hypercholesterolemia was associated with lower CV mortality. OAC use significantly reduced CV but not non-CV mortality (Figure 3B,C).
Because the therapeutic strategies for AF changed after the publication of the Guidelines for the Pharmacotherapy of Atrial Fibrillation (JCS2008), 17 patients' background information and prognostic factors were also assessed by categorizing them into 2 groups depending on whether they started to be observed before 2009 or in 2009 and later. Patients who started being observed before 2009 were significantly younger than those who began being observed in 2009 or later, but there were no significant 389 patients, 61% were taking OACs. There were 171 deaths during the follow-up period. The patients who died during the follow-up period were significantly older and had a higher prevalence of comorbidities, such as previous stroke and sustained AF, but the CHA2DS2-VASc scores were equivalent between those who died and those who did not (Table 1A). Table 2A details of the cause of death in all patients and in patients stratified according to age. Of the patients who died during the follow-up period, approximately 30% died of CV causes, <50% died of non-CV causes, and 25% died of unknown causes. CV death included heart failure (13%), sudden death (9%), and stroke (only 2%). Non-CV death included malignant neoplasm (19%), pneumonia (11%), senility (6%), and infection (5%). Elderly AF patients were likely to die from non-CV causes. The survival curves stratified by cause of death for the entire study population are shown in Figure 2. The event rate of all-cause death, non-CV death, and CV death was 2.6%, 1.2%, and 0.7% per year, respectively.
In the multivariate Cox regression analysis (Figure 3A), baseline variables associated with all-cause death were age

Discussion
The present analysis revealed that almost half the deaths in elderly AF patients were due to non-CV causes and that one-third of deaths were from CV causes. The most common cause of CV death was heart failure, which was the second leading cause of death after malignant neoplasm, followed by pneumonia. Only 2% of all-cause death was due to stroke. Diabetes was the factor most strongly associated with a higher incidence of non-CV death. Pre-existing heart failure was associated with CV and non-CV death, but in opposite directions.

Cause of Death in Elderly AF Patients
Compared with previous cohort studies, [9][10][11][12] the patients in the present study were older, had a higher CHA2DS2-VASc score, a longer observation period, and equivalent OAC use and mortality. The causes of death were similar to those reported in previous studies, 9-12 including the predominance of non-CV death, malignant neoplasm, heart failure, and pneumonia, and fewer stroke deaths. A distinguishing feature of the present study is that 6% of total deaths were

Cause of Death in Elderly AF Patients
outcome. It is unclear why pre-existing heart failure was associated with better non-CV mortality. No studies to date have demonstrated that pre-existing heart failure is associated with better mortality risk. The Fushimi AF Registry demonstrated that pre-existing heart failure was

Comorbidities and Mortality Risk
The significant finding of the present analysis was that the mortality risk associated with pre-existing heart failure differs between CV and non-CV deaths. Pre-existing heart failure was associated with a worse CV, but better non-CV and body weight, the greater the risk of frailty. 20 The patients in the present study were older and more likely to be frail than the other cohorts, resulting in hypertension and hypercholesterolemia being associated with a better prognosis. Because elderly AF patients have many comorbidities, both anticoagulation therapy for stroke prevention and optimal treatment of each comorbidity are required for a better prognosis in this group of patients. To establish the ideal treatment for prolonging a healthy life expectancy of these patients, we must pay attention not only to a single disease, but also to the whole body and all comorbidities.

Future Perspectives
The treatment of AF patients has been focused on the prevention of thromboembolism. Direct oral anticoagulants have not only enabled the effective prevention of stroke, but also enhanced the safety of this group of patients. 27-30 However, the results of real-world cohort studies indicate that although OACs reduce all-cause mortality, their reduction of stroke deaths, a primary purpose for their use, is minimal. Moreover, heart failure, renal failure, anemia, and lung disease are associated with a poor prognosis. Geriatric patients have many comorbid conditions, most of which are associated with their prognosis; as a result, interventions targeting a single disease may have limited efficacy in this population. 3 A single disease-specific therapeutic strategy for patients with this condition may have little effect on the morbidities or mortality of the individual. associated with high CV mortality, but not non-CV mortality. 10 Studies evaluating the association between preexisting heart failure and non-CV death indicated greater mortality 12 or no association. 10 One potential reason for this paradoxical finding is the diagnosis of heart failure. In the present study, patients were diagnosed with heart failure if they had a history of heart failure, regardless of heart failure status. As a result, many survivors are likely to be well treated. Elderly AF survivors with pre-existing heart failure may be well treated, resulting in a better prognosis. They may be a biased population, leading to reverse causation.
Cardiometabolic risk factors such as hypertension, dyslipidemia, diabetes, and obesity are well-known factors that accelerate the lifetime risk for CV disease. 23 Current guidelines require optimal levels of these metabolic factors for the prevention of CV disease. [13][14][15] In contrast, in elderly AF patients, the association of these cardiometabolic factors with mortality has not been fully evaluated. Some studies report that hypertension is associated with a better prognosis. 9,11, 24 The Fushimi AF registry demonstrated that statin use, suggestive of dyslipidemia, is associated with better all-cause mortality. 10 Moreover, the trajectories of blood pressure 25 and total cholesterol levels 26 exhibit an accelerated decline in the last years of life through frailty. In a previous evaluation of cardiometabolic risk control in frail outpatients, we found that the more controlled the cardiometabolic risk factors, such as blood pressure, lipids, The Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria (Steno-2) trial investigated type 2 diabetic patients with albuminuria and demonstrated additive reductions in CV events and death by lowering lipid and blood pressure levels in addition to blood glucose control, indicating the importance of comprehensive risk control for improving the prognosis of these patients. 31 The current treatment of elderly AF patients may focus too much on stroke prevention and too little on the management of comorbidities. Because of the likelihood of comorbidities in AF patients, comprehensive treatment for multiple disorders is required to prolong the healthy life expectancy of these patients.

Study Limitations
The present study has several limitations. First, the results of the study were derived from a retrospective observational study, showing only the association and not the causation.
Second, the quality of anticoagulation by warfarin and adherence to OAC regimens were not investigated. Third, the percentage of deaths of unknown cause among all-cause deaths was relatively high (26%), resulting in an underestimation of each specified cause of death, such as stroke or other CV causes. However, this percentage is comparable with other real-world cohort studies, such as the GARFIELD-AF and FUSHIMI registries. 9,10 Fourth, the present study was conducted in a relatively limited area and number of institutes, and so the results cannot be generalized. Finally, this study included patients who started to be observed in an era when direct oral anticoagulants were not available. However, a study evaluating the long-term prognosis in new-onset AF patients indicated no difference in mortality across the different time periods. 32 These issues should be considered when interpreting the results of the present analysis.

Conclusions
In elderly Japanese AF patients, non-CV deaths (mainly infection and pneumonia) predominated. Heart failure, not stroke, was the predominant CV death regardless of the age group. Clinical factors that were associated with CV and non-CV deaths were distinct. These findings provide important information for the optimal treatment of elderly AF patients for a better prognosis.