Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　― Results From the ANAFIE Registry ―

Abstract

Background: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era.

Methods and Results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease.

Conclusions: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

Atrial fibrillation (AF) is a common arrhythmia among the elderly population and is associated with an increased risk of stroke.¹ Anticoagulant therapy with oral anticoagulants (OACs) in AF has been reported to prevent stroke/systemic embolic events,^2–6 and is recommended in a number of guidelines.^7,8 However, the prognosis of patients with AF is poorly understood; this particularly applies to aging or elderly patients with AF, whose population is increasing markedly in Japan.

Although AF is associated with the risk of stroke, causes of death other than stroke remain unclear and have been reported mainly in clinical trials.^9–11 There are only a limited number of reports of real-world analysis of causes of death in elderly patients with AF.^12–14 Furthermore, these previous studies included a limited number of elderly patients (age ≥75 years) receiving direct OACs (DOACs). A detailed analysis of the causes of death in elderly Japanese patients with AF receiving DOACs would help optimize treatment in this patient population.

The All Nippon AF In the Elderly (ANAFIE) Registry was a real-world study conducted from October 2016 to January 2020 that evaluated the clinical status and prognosis of over 30,000 elderly Japanese patients with non-valvular AF (NVAF). The baseline data and 2-year outcomes of the ANAFIE Registry have been published previously.^15,16 We conducted a subanalysis of the ANAFIE Registry to clarify the 2-year mortality rate according to causes of death of elderly NVAF patients in the DOAC era.

Methods

Study Design

The design of the ANAFIE Registry has been described previously.¹⁷ Briefly, the ANAFIE Registry was a multicenter prospective observational real-world study, with patient enrollment from October 2016 to January 2018.

The ANAFIE Registry was conducted in accordance with the Declaration of Helsinki, local requirements for registries, and ethical guidelines for clinical studies in Japan. Ethics committee approvals were obtained from each participating study center. All participants or their family members provided written informed consent. The main study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000024006.

Patients

The study included patients with a definite diagnosis of NVAF confirmed by electrocardiography who were aged ≥75 years at the time of informed consent and who were able to attend study visits. Exclusion criteria have been reported previously.¹⁷

Outcomes

The outcomes of interest for the present subanalysis were causes of death, which were classified as presented in Table 1.¹¹ “Other” deaths included undetermined, natural death from old age and other causes of death. Comparisons were made between patients aged <85 and ≥85 years.

Table 1. Outcome of Interest: Categories of Causes of Death

1. Cardiovascular death

a. Fatal bleeding

i. Intracranial hemorrhage

ii. Extracranial bleeding

b. Non-bleeding cardiovascular death

i. Ischemic stroke

ii. Systemic embolic event

iii. Congestive heart failure or cardiogenic shock

iv. Coronary revascularization

v. Arrhythmia

vi. Pulmonary embolism

vii. Sudden or unwitnessed death

viii. Arteriosclerotic vascular disease

ix. Other causes

2. Death caused by malignancy

3. Other deaths

a. Infection

b. Suicide

c. Accidents/trauma

d. Hepatobiliary disease

e. Renal disease

f. Other causes (i.e., undetermined, natural death, and others)

Statistical Analysis

Among the patients enrolled in the ANAFIE Registry, those who died during the follow-up period were investigated. Data were analyzed in the analysis set, defined as all enrolled patients, excluding those with any protocol violation, those without follow-up visits after providing informed consent, and those excluded for other reasons. Cause of death was determined by treating physicians, and the distribution of causes of death was investigated by patient age and type of OAC. Adjusted hazard ratios (HRs) for DOACs vs. warfarin and no OAC vs. warfarin were calculated for each cause of death using the Cox proportional hazards model with the following covariables: sex, age, body mass index, history of major bleeding, type of AF, systolic blood pressure, severe hepatic disease, diabetes, hyperuricemia, heart failure and/or reduced left ventricular ejection fraction, myocardial infarction, cerebrovascular disease, thromboembolic disease, active cancer, fall within 1 year, catheter ablation, antiarrhythmics, antiplatelet agents, proton pump inhibitors, P-glycoprotein inhibitors, dyslipidemia, creatinine clearance, gastrointestinal disease, and polypharmacy. Tests were 2-sided, and P<0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Tokyo, Japan).

Results

Patients

Of the 33,062 patients enrolled in the ANAFIE Registry, 32,275 were included in the analysis set.¹⁶ The mean follow-up period was 1.88 years. Details of patient disposition have been provided previously.¹⁶

The mean age of patients was 81.5 years, and 57.3% (n=18,482) were male. The mean CHA₂DS₂-VASc and HAS-BLED scores were 4.5 and 1.9, respectively. The prevalence of paroxysmal AF was 42.1% (n=13,586). The proportion of patients using OACs was 92.4% (n=29,830); among these patients, 66.9% (n=21,585) were using DOACs and 25.5% (n=8,233) were using warfarin.¹⁶

Outcomes

Among the patients who completed the study survey at 24 months, 2,242 patients (6.9%) died. Of these, 1,167 (52.1%) were aged <85 years and 1,075 (47.9%) were aged ≥85 years at enrollment.

The causes of death in the total population and in those aged <85 and ≥85 years are shown in Figure 1. In the overall population, cardiovascular deaths were observed in 727 (32.4%) patients, malignancy-related deaths were observed in 360 (16.1%) patients, and death for other reasons was observed in 1,155 (51.5%) patients. Among cardiovascular deaths, the most common causes of death were congestive heart failure or cardiogenic shock (11.8%), followed by sudden or unwitnessed death (6.2%), ischemic stroke (3.8%), intracranial hemorrhage (3.7%), extracranial bleeding (3.1%), and others (3.3%). Among other deaths, 17.1% were related to infection, 2.4% were related to renal disease, and 31.3% were related to other causes; approximately two-thirds of these other causes of death were undetermined, and the remaining one-third were attributed to deaths from old age and respiratory diseases. Apparent differences were observed in the distribution of causes of death between patients aged <85 and ≥85 years. In patients aged ≥85 years, the proportion of malignancy-related death decreased, whereas that of death for other reasons increased, compared with patients aged <85 years.

Figure 1.

Causes of death in the total population and in those aged <85 and ≥85 years separately.

In the overall population, the incidence rates of cardiovascular death, malignancy-related death, and death due to infection were 1.20, 0.60, and 0.63 per 100 person-years (Figure 2A). Compared with patients aged <85 years (Figure 2B,C), those aged ≥85 years showed numerically higher incidence rates (per 100 person-years) of cardiovascular death (0.81 vs. 2.37), death due to congestive heart failure or cardiogenic shock (0.27 vs. 0.94), malignancy-related death (0.52 vs. 0.82), death due to infection (0.42 vs. 1.27), and death due to renal disease (0.05 vs. 0.21).

Figure 2.

Incidence rates of events in (A) the overall population and in those aged (B) <85 and (C) ≥85 years. Whiskers indicate 95% confidence intervals. “Other” deaths included undetermined, natural death from old age, and other causes of death.

The results of univariate and multivariate analyses of causes of death by type of anticoagulant (DOAC vs. warfarin and no OAC vs. warfarin) are summarized in Table 2. Compared with warfarin use, DOAC use was associated with a significantly lower risk of cardiovascular death (adjusted [a] HR 0.78; 95% confidence interval [CI] 0.66–0.92; P=0.003) and other death (aHR 0.81; 95% CI 0.72–0.93; P<0.002). A comparison of causes of death showed that differences in cardiovascular deaths were due to death by intracranial hemorrhage (aHR 0.58; 95% CI 0.37–0.91; P=0.019) and ischemic stroke (aHR 0.58; 95% CI 0.36–0.91; P=0.018). The differences in other deaths were due to death by renal disease (aHR 0.47; 95% CI 0.25–0.87; P=0.017) and other causes (aHR 0.80; 95% CI 0.67–0.94; P=0.007). Compared with warfarin use, no OAC use was associated with a significantly higher risk of other deaths (aHR 1.31; 95% CI 1.06–1.61; P=0.012), including death due to infection (aHR 1.67; 95% CI 1.17–2.38; P=0.004).

Table 2. Cox Proportional Hazards Model Results of Univariate and Multivariate Analyses of Causes of Death by Type of Anticoagulant Used

Variable	Anticoagulant	No. patients	No. events (%)	Univariate		Multivariate
				HR (95% CI)	P value	HR (95% CI)	P value
Cardiovascular death	Warfarin*	8,233	261 (3.2)	–		–
	No OAC	2,445	78 (3.2)	1.02 (0.79–1.31)	0.874	1.28 (0.98–1.67)	0.066
	DOAC	21,585	388 (1.8)	0.56 (0.48–0.65)	<0.001	0.78 (0.66–0.92)	0.003
Intracranial hemorrhage	Warfarin*	8,233	35 (0.4)	–		–
	No OAC	2,445	5 (0.2)	0.49 (0.19–1.25)	0.134	0.48 (0.18–1.25)	0.132
	DOAC	21,585	44 (0.2)	0.47 (0.30–0.73)	<0.001	0.58 (0.37–0.91)	0.019
Extracranial bleeding	Warfarin*	8,233	27 (0.3)	–		–
	No OAC	2,445	6 (0.2)	0.76 (0.31–1.83)	0.539	0.77 (0.31–1.92)	0.568
	DOAC	21,585	37 (0.1)	0.51 (0.31–0.84)	0.008	0.65 (0.39–1.09)	0.104
Ischemic stroke	Warfarin*	8,233	35 (0.4)	–		–
	No OAC	2,445	7 (0.3)	0.68 (0.30–1.54)	0.359	1.23 (0.53–2.89)	0.631
	DOAC	21,585	43 (0.2)	0.46 (0.29–0.72)	0.001	0.58 (0.36–0.91)	0.018
Systemic embolic event	Warfarin*	8,233	2 (0.0)	–		–
	No OAC	2,445	0 (0.0)	0.00 (–)	–	0.00 (–)	–
	DOAC	21,585	3 (0.0)	0.56 (0.09–3.33)	0.521	1.19 (0.17–8.54)	0.862
CHF or CS	Warfarin*	8,233	97 (1.2)	–		–
	No OAC	2,445	30 (1.2)	1.06 (0.70–1.59)	0.789	1.50 (0.98–2.30)	0.064
	DOAC	21,585	138 (0.6)	0.53 (0.41–0.69)	<0.001	0.82 (0.63–1.07)	0.144
Pulmonary embolism	Warfarin*	8,233	1 (0.0)	–		–
	No OAC	2,445	0 (0.0)	0.00 (–)	–	0.00 (–)	–
	DOAC	21,585	2 (0.0)	0.74 (0.07–8.20)	0.809	–	–
Sudden or unwitnessed death	Warfarin*	8,233	43 (0.5)	–		–
	No OAC	2,445	17 (0.7)	1.35 (0.77–2.37)	0.296	1.59 (0.88–2.87)	0.125
	DOAC	21,585	78 (0.4)	0.68 (0.47–0.99)	0.043	0.90 (0.61–1.32)	0.591
Others	Warfarin*	8,233	21 (0.3)	–		–
	No OAC	2,445	12 (0.5)	1.95 (0.96–3.96)	0.066	2.08 (0.98–4.41)	0.057
	DOAC	21,585	40 (0.2)	0.71 (0.42–1.21)	0.211	1.13 (0.65–1.94)	0.668
Malignancy	Warfarin*	8,233	86 (1.0)	–		–
	No OAC	2,445	29 (1.2)	1.15 (0.76–1.75)	0.512	1.24 (0.80–1.92)	0.337
	DOAC	21,585	245 (1.1)	1.07 (0.83–1.36)	0.609	1.15 (0.90–1.48)	0.269
Other deaths	Warfarin*	8,233	381 (4.6)	–		–
	No OAC	2,445	128 (5.2)	1.15 (0.94–1.40)	0.178	1.31 (1.06–1.61)	0.012
	DOAC	21,585	645 (3.0)	0.63 (0.56–0.72)	<0.001	0.81 (0.72–0.93)	0.002
Infection	Warfarin*	8,233	114 (1.4)	–		–
	No OAC	2,445	49 (2.0)	1.47 (1.05–2.05)	0.025	1.67 (1.17–2.38)	0.004
	DOAC	21,585	220 (1.0)	0.72 (0.58–0.91)	0.005	0.92 (0.73–1.16)	0.475
Suicide	Warfarin*	8,233	1 (0.0)	–		–
	No OAC	2,445	0 (0.0)	0.00 (–)	–	0.00 (–)	–
	DOAC	21,585	4 (0.0)	1.50 (0.17–13.45)	0.716	1.50 (0.16–14.13)	0.721
Hepatobiliary disease	Warfarin*	8,233	3 (0.0)	–		–
	No OAC	2,445	3 (0.1)	3.42 (0.69–16.93)	0.132	6.70 (0.92–48.99)	0.061
	DOAC	21,585	4 (0.0)	0.50 (0.11–2.24)	0.364	0.36 (0.06–2.03)	0.248
Renal disease	Warfarin*	8,233	26 (0.3)	–		–
	No OAC	2,445	9 (0.4)	1.18 (0.56–2.53)	0.661	1.47 (0.64–3.36)	0.367
	DOAC	21,585	18 (0.1)	0.26 (0.14–0.47)	<0.001	0.47 (0.25–0.87)	0.017
Other causes	Warfarin*	8,233	237 (2.9)	–		–
	No OAC	2,445	66 (2.7)	0.95 (0.72–1.25)	0.719	1.07 (0.80–1.42)	0.643
	DOAC	21,585	397 (1.8)	0.63 (0.53–0.74)	<0.001	0.80 (0.67–0.94)	0.007

*Warfarin was used as the reference group. CHF, congestive heart failure; CI, confidence interval; CS, cardiogenic shock; DOAC, direct oral anticoagulant; HR, hazard ratio; OAC, oral anticoagulant.

Discussion

The present subanalysis of the ANAFIE Registry clarified the distribution of causes of death in elderly Japanese patients with NVAF. In the overall population, cardiovascular death and deaths due to infection and malignancy accounted for 32.4%, 17.1%, and 16.1% of the total mortality, respectively. Among cardiovascular deaths, the proportion of deaths due to ischemic stroke, intracranial hemorrhage, and extracranial bleeding was 3.8%, 3.7%, and 3.1%, respectively. The most common cardiovascular deaths were related to congestive heart failure or cardiogenic shock (11.8%) and sudden or unwitnessed death (6.2%), whereas deaths for other reasons accounted for 51.5% of total deaths, with the most common reason being infection (17.1%).

Causes of death in AF patients have been reported in several randomized clinical trials^9–11 and observational studies.^12–14 Data from 4 large-scale clinical trials showed that cardiovascular death accounted for 64% of the total mortality, with heart failure and sudden death predominant, and ischemic stroke and hemorrhage-related death represented only approximately 6%.¹⁸ The proportion of non-cardiovascular death was relatively small (30%), and malignancy and infection accounted for 11% and 9%, respectively.¹⁸ Meanwhile, real-world data have shown somewhat different results. The Fushimi AF Registry revealed that non-cardiovascular death accounted for 54% of the total mortality, with malignancy and infection accounting for 23% and 17%, respectively.¹³ Other registries and observational studies also showed that non-cardiovascular death accounted for 36–66% of the total mortality.^19–21 These differences may reflect strict selection criteria of physicians and patients at enrollment in the randomized clinical trials. The present prospective observational study showed that cardiovascular death accounted for 32.4% of total mortality, similar to previous observational studies.^12,13 In addition, the findings of the present study suggest that patient age affects the proportion of causes of death: higher patient age was associated with an increase in non-cardiovascular deaths, including infection, and a decrease in malignancy-related deaths.

The present study also showed that the incidence rates of several causes of death tended to be higher among patients aged ≥85 years than among those aged <85 years, as expected. For example, in addition to malignancy-related death, the incidence rates of cardiovascular death, including heart failure or cardiogenic shock, ischemic stroke, intracranial hemorrhage, death due to infection, and renal disease were approximately 3- to 4-fold higher in patients aged ≥85 years than in those aged <85 years. Notably, the incidence rates of death due to ischemic stroke and intracranial hemorrhage were much lower than those of other causes of death in the ANAFIE Registry in both age groups, in which more than 90% of patients were under anticoagulation.

DOAC use was associated with reduced death due to intracranial bleeding and ischemic stroke compared with warfarin, a finding consistent with previous reports.^9–11 Mortality due to ischemic stroke in the present study was more markedly decreased than that reported in a previous study with warfarin,²² and this difference may be attributable to the widespread use of DOACs in the present study. Furthermore, DOAC use was associated with decreased deaths due to renal disease. The reasons for this are unclear, but previous reports have suggested that DOACs may be more likely to maintain renal function than warfarin,^23–25 although other confounding factors should be considered. This analysis of the association between DOAC usage and mortality according to deaths should shed light on the significance of other causes of death not affected by DOAC use, particularly congestive heart failure or cardiogenic shock, in the prognosis of elderly AF patients.

Both dementia and frailty are associated with older age and may affect the cause of death. In the ANAFIE Registry, patients with dementia and frail patients were included in the analysis, and dementia was identified as a risk factor for all-cause death (HR 1.78; 95% CI 1.59–2.00; P<0.001).¹⁶ Regarding frailty, we previously reported that stroke/systemic embolism, major bleeding, and all-cause death were significantly higher in the frail group than in the robust and prefrail groups.²⁶

The limitations of the ANAFIE Registry have been described previously.¹⁶ The present subanalysis is limited by its observational study design, and it is possible that not all causes of death were fully elucidated. Furthermore, the treating physician determined the cause of death rather than an independent committee. Multivariate analysis of the association between warfarin and DOAC would not be free from undetermined confounding factors. Moreover, the present results were drawn from a landmark analysis, and there was no information on when OAC was discontinued before death. Finally, data on patients lost to follow-up were not analyzed by age.

In conclusion, in elderly Japanese patients with NVAF, intracranial events (ischemic stroke or intracranial hemorrhage) accounted for 7.5% of the causes of death, with heart failure-related deaths having a higher impact (11.8%). Infection- and malignancy-related deaths were also more common in this patient population (17.1% and 16.1%, respectively). The distribution and the incidence rates of these events were affected by patient age. DOAC use was associated with a significantly lower risk of death due to intracranial hemorrhage, ischemic stroke, and renal disease than warfarin use. These results reiterate the importance of the holistic management of elderly patients with NVAF in the DOAC era, including anticoagulant therapy to prevent stroke and other possible therapies for comorbidities, such as heart failure, infection, or cancer.

Acknowledgments

The authors thank all individuals (physicians, nurses, institutional staff, and patients) involved in the ANAFIE Registry. The authors also thank IQVIA Services Japan K.K. and EP-CRSU for their partial support in the conduct of this Registry, and Michelle Belanger, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd., in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022). In addition, the authors thank Daisuke Chiba, of Daiichi Sankyo Co., Ltd., for providing support in the preparation of this manuscript.

Sources of Funding

This study was supported by Daiichi Sankyo Co., Ltd.

Disclosures

T. Yamashita has received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo; manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb; and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. M.A. has received research funding from Bayer and Daiichi Sankyo; and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.A. has received remuneration from Daiichi Sankyo. T.I. has received research funding from Daiichi Sankyo and remuneration from Daiichi Sankyo, Bayer, and Pfizer Japan. Y.K. has received remuneration from Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. K.O. has received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. W.S. has received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim; and remuneration from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. S.S. has received research funding from Daiichi Sankyo and remuneration from Bristol-Myers Squibb and Daiichi Sankyo. H.T. has received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim; remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan; scholarship funding from Daiichi Sankyo; and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. K.T. has received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Otsuka, Novartis, and Abbott Medical. A.H. has participated in a course endowed by Boston Scientific Japan; has received research funding from Daiichi Sankyo and Bayer; and has received remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. M.Y. has received research funding from Nippon Boehringer Ingelheim and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer Japan. T. Yamaguchi has acted as an advisory board member for Daiichi Sankyo and has received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. S.T. has received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, Kaneka, Kringle Pharma, and Atworking. T.K., Y.M., and A.T. are employees of Daiichi Sankyo. H.I. has received remuneration from Daiichi Sankyo, Bayer, and Bristol-Myers Squibb, and consultancy fees from Daiichi Sankyo. T. Yamashita, H.T., W.S., T.I., and A.H. are members of Circulation Journal’s Editorial Team.

Author Contributions

T. Yamashita, M.A., H.A., T.I., Y.K., K.O., W.S., S.S., H.T., K.T., A.H., M.Y., T. Yamaguchi, and H.I. designed and conducted the study. T. Yamashita interpreted the data analysis. S.T. performed the statistical analyses. T. Yamashita, T.K., Y.M., and A.T. wrote and reviewed the manuscript. All authors revised and commented on the manuscript and approved the final version.

IRB Information

Ethics approval was obtained from all relevant institutional review boards, and all patients provided written informed consent and were free to withdraw from the Registry at any time. The principal ethics committee was The Ethics Committees of The Cardiovascular Institute (Tokyo, Japan; Approval no. 299).

Data Availability

The individual deidentified participant data and study protocol will be shared for up to 36 months after publication of the article. Access criteria for data sharing (including requests) will be decided on by a committee led by Daiichi-Sankyo. To gain access, those requesting data access will need to sign a data access agreement. Requests should be directed to [e-mail]

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