Association Between Atrial High-Rate Episodes and Ischemic/Major Bleeding Events in Patients With a Cardiac Implantable Electronic Device　― A 10-Year, Single-Center Historical Cohort Study ―

Abstract

Background: An association between atrial high-rate episode (AHRE) and stroke has been reported, although data for the Asian population are limited. This study aimed to investigate the role of AHRE in ischemic and major bleeding events in patients who underwent a cardiac implantable electronic device (CIED) procedure.

Methods and Results: This single-center historical cohort study included 710 patients (age: 78±11 years, 374 women) who underwent a CIED-related procedure between October 2009 and September 2019 at Shimane Prefectural Central Hospital (median follow-up period: 4.5 [2.5, 7] years, 3439 person-years). Based on the maximum AHRE burden, patients were divided into: (1) <6 min; (2) ≥6 min to 24-h; and (3) ≥24-h groups. The cumulative incidence of ischemic (ischemic stroke, systemic embolism, and transient ischemic attack) and major bleeding (≥3 Bleeding Academic Research Consortium bleeding criteria) events after the procedure were compared. Uni- and multivariate analyses were performed to identify factors associated with these events. The incidence of both events increased with the rising AHRE burden, being significantly higher in the ≥24-h group than in the <6 min group. Multivariate analysis found age ≥85 years to be the only independent factor associated with both events.

Conclusions: Longer AHRE duration is associated with a high number of major bleeding and ischemic events. Monitoring these bleeding risks is mandatory when clinicians are considering anticoagulation therapy for such patients.

Atrial fibrillation (AF) is the most common atrial arrhythmia worldwide.¹ Its prevalence is estimated to rise linearly, with an increasing aged population.² Ischemic events such as ischemic stroke and systemic thromboembolism are some of the main complications of AF, resulting in high mortality, health-care burden, and impairment of quality of life.³ In patients receiving cardiac implantable electronic devices (CIEDs), including pacemakers and implantable cardioverter defibrillators, and cardiac resynchronization therapy, information on the atrial high-rate episode (AHRE), which predominantly includes AF, can be acquired from an atrial electrogram. Previous studies from Western countries have shown a 2- to 3-fold higher risk of ischemic events in patients with an AHRE than those without it.^4-7 Furthermore, the risk could be particularly elevated in patients with a long-duration AHRE (>24 h).⁸ Although there is a large amount of evidence associating AHRE with ischemic events, the data for Asian patients are limited. Additionally, even in non-Asian populations, the risk evaluation for major bleeding and ischemic events in patients with AHRE is limited. One might presume that patients with AHRE are at a higher risk of both ischemic events and major bleeding in response to the increased duration of AHRE, thereby suggesting that both these events share common risk factors.⁹ Given that Asian patients with AF are at a higher risk of major bleeding than non-Asian populations,^10,11 it is crucial to assess the effect of AHRE on this risk in the Asian population.

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Therefore, we aimed to investigate the association between the incidence of ischemic/major bleeding events and the duration of AHRE through a retrospective analysis of patients who underwent CIED-related procedures at Shimane Prefectural Central Hospital. We also sought to identify factors associated with both events.

Methods

Study Design and Data Collection

This single-center historical cohort study was conducted at the Shimane Prefectural Central Hospital, a tertiary general hospital in Japan. The Institutional Review Board of our hospital approved the study in July 2020. The requirement for informed patient consent was waived due to the retrospective design of the study. The study information was disclosed on our institutional website owing to the opt-out system.

Data collection and enrollment of patients were performed by reviewing the electronic medical records, as previously described.¹² Consecutive patients who underwent CIED-related procedures in the cardiac catheterization laboratory between October 2009 and September 2019 were enrolled. Patients who underwent multiple procedures during the study period were considered only for the initial procedure. Patients who had a VVI pacemaker implanted, lacked information on AHRE or died within 6 months after the procedure were excluded from the study. CIED-related procedures were categorized as de novo, exchange, and revision. De novo procedures were related to the first implantation, whereas exchange involved a simple generator change, and revision was for correcting generator/lead position, hematoma evacuation, and implanting additional leads (atrial, right/left ventricular, or defibrillation leads), as previously described.¹² AHRE was defined as an atrial arrhythmia of >175 beats/min.^5,6,13 Based on the maximum AHRE burden during the entire follow-up period, we classified the patients into 3 groups: (1) <6 min, (2) ≥6 min to 24 h, or (3) ≥24 h. The basis of using AHRE burden for dividing each group was established in a previous study.⁴ The study defined significant burden at a time point of more than 6 min. Furthermore, the subanalysis of the study revealed that the maximum burden of more than 24 h was only associated with significant increased risk of stroke events.⁸ Hence, we divided our study population into the aforementioned 3 groups. The cumulative incidence of ischemic and major bleeding events and baseline clinical variables were compared among these groups. In addition, the clinical variables were also compared between patients who did and did not develop ischemic/major bleeding events. Uni- and multivariate analyses were performed to identify factors associated with clinical events.

Patients Follow up

Patients underwent an ambulatory follow up every 3–6 months at our institution. The records related to the maximum duration, heart rate, rhythm of AHRE, and antithrombotic drugs (antiplatelet agents or anticoagulants) were obtained from the follow ups. The initiation of antithrombotic drugs was at the discretion of the primary care doctors. A 12-lead electrocardiogram was recorded at every follow up. If AF was confirmed by a 12-lead electrocardiogram in patients with a high thromboembolic risk (e.g., CHADS₂ score of ≥2),¹⁴ we recommended the initiation of anticoagulation therapy by their primary care doctors. Regarding patients who changed institutions for follow up, we contacted for the institutions about the information for AHRE and clinical events.

Clinical Events

Clinical events were defined as ischemic and major bleeding events occurring after a week following the CIED-related procedure. Ischemic events included ischemic stroke, transient ischemic attack (TIA), and systemic embolism (SE). Major bleeding events were defined as events of grade ≥3 as per the Bleeding Academic Research Consortium (BARC) bleeding criteria (grade 3: overt clinical bleeding with ≥3–5 g/dL hemoglobin decline, requiring transfusion of ≥2 units, or requiring surgery for hemostasis, and grade 5: fatal bleeding).¹⁵

Clinical Variables

Clinical variables such as body weight (BW), history of AF, hemoglobin, estimated glomerular filtration rate (eGFR), brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF) and left atrial diameter (LAD) were collected within a week following the CIED procedure. CHADS₂ (congestive heart failure: 1, hypertension: 1, age ≥75 years: 1, diabetes mellitus: 1, and history of stroke: 2), CHA₂DS₂-VASc (CHADS₂ with vascular disease: 1, age ≥65 years: 1, and female sex: 1) and HAS-BLED (hypertension with a systolic blood pressure of ≥160 mmHg: 1, abnormal renal and/or liver function: 1 or 2, history of stroke: 1 and bleeding: 1, liable INRs (time in therapeutic range of less than 60%): 1, age ≥65 years: 1, and drugs and/or alcohol: 1 or 2) scores^16–18 were calculated at the time of discharge following the CIED-related procedure. Information on the use of antiplatelet agents (acetylsalicylic acid or P2Y₁₂ inhibitors) and anticoagulants (a vitamin K antagonist [VKA] or direct oral anticoagulant [DOAC]) was collected just before the censoring point (last follow up or clinical events).

Statistical Analysis

Normally distributed variables were expressed as mean±standard deviation, whereas non-normally distributed variables were expressed as a median and interquartile (first and third) range. Differences in continuous variables between the 2 groups were evaluated using the Mann-Whitney U-test. Categorical variables have been presented as frequency and proportion (%) and were compared using the chi-squared (χ²) test. The differences between the 3 groups based on the maximum AHRE burden were evaluated using the Kruskal-Wallis test. The differences in the cumulative incidence of clinical events in these groups were compared by using the log-rank test.

To evaluate if clinical events trends in each group persisted in a similar background population, we performed the log-rank test in patients who underwent the first procedure (de novo) in each group as a sensitivity analysis. Additionally, we performed another sensitivity analysis to evaluate whether the trends of clinical events in each group persisted even in a population that excluded patients who were previously diagnosed with AF. Cox proportional hazards regression analysis was performed to identify factors associated with the development of clinical events in the total population. Variables such as age ≥85 years, BW, history of AF, implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy (CRT), CHADS₂ score of ≥4, HAS-BLED score of ≥3, an AHRE burden of ≥24 h, eGFR of <30 mL/min/1.73 m², LAD of ≥40 mm, and use of antiplatelet agents and VKA/DOAC were evaluated by univariate analysis. Variables with a P value ≤0.05 were entered into a subsequent multivariate analysis. To evaluate the association between a long duration of AHRE burden and clinical events, an AHRE burden of ≥24 h was entered into multivariate analysis, irrespective of the result of univariate analysis.

The results were expressed as hazard ratio (HR) and 95% confidence interval (CI). All analyses were performed using SPSS version 19 (SPSS, Inc., Chicago, IL, USA) and GraphPad Prism version 5 (GraphPad Software, Inc. San Diego, CA, USA), and results with a P value <0.05 were considered statistically significant.

Results

Study Population

The study flow diagram is shown in Figure 1. We enrolled a total of 710 patients. The median follow-up period was 4.5 (range: 2.5–7) years (3,439 person-years). The median follow-up period was significantly longer in the ≥24 h group followed by the ≥6 min to 24 h group, with the <6 min group having the shortest follow-up period (5 [2.9, 7.8] years [798 person-years] vs. 4.8 [3, 6.8] years [1,004 person-years] vs. 3.8 [2.2, 6.7] years [1,637 person-years], respectively; P=0.004).

Figure 1.

Flow diagram of the study. AHRE, atrial high rate episode; CIED, cardiovascular implantable electronic device.

Of these patients, 32% (230/710) died during the follow-up period. The proportion of cardiovascular mortality was 27% (64/230 patients). During the entire follow-up period, the first AHRE was detected at a median of 0.5 (0.1, 1) year following the CIED-related procedure. The characteristics of patients in each group are shown in Table 1. The mean age and mortality were comparable among the groups. The AHRE burden ≥24 h group had significantly higher CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores compared to the other 2 groups. The prevalence of a history of AF, prescribed VKA, and DOAC increased with the AHRE burden. The LAD also enlarged with the increase in the AHRE burden.

Table 1. Patient Characteristics

	Total (n=710)	<6 min (n=360)	≥6 min to 24 h (n=201)	≥24 h (n=149)	P value
Age (years), mean±SD	78±11	78±11	78±10	77±10	0.53
Female, n (%)*	374 (53)	203 (56)	105 (52)	66 (44)	0.045
History of AF, n (%)*	206 (29)	3 (1)	88 (44)	115 (77)	<0.0001
BW (kg), mean±SD	53±11	53±11	53±11	55±11	0.09
1st procedure (de novo), n (%)*	564 (79)	300 (83)	152 (76)	112 (75)	0.03
ICD, n (%)*	44 (6)	35 (10)	4 (2)	5 (3)	0.0004
CRT, n (%)*	82 (12)	38 (11)	15 (7)	29 (19)	0.001
Number of leads, mean±SD	2.1±0.5	2.1±0.5	2.0±0.4	2.1±0.5	0.07
SSS, n (%)*	266 (37)	86 (24)	96 (48)	84 (56)	<0.0001
AVB, n (%)*	293 (41)	170 (47)	80 (40)	43 (29)	<0.0001
CHADS2, mean±SD*	2.4±1.1	2.3±1.1	2.3±1.2	2.7±1.2	0.0009
CHA2DS2-VASc, mean±SD*	4.0±1.4	3.9±1.4	3.9±1.4	4.2±1.4	0.02
HAS-BLED, mean±SD	1.9±1.0	1.8±1.1	1.9±1.0	2.0±1.1	0.15
Hemoglobin (g/dL), mean±SD	12.4±1.9	12.4±1.9	12.3±1.9	12.7±1.8	0.14
eGFR (mL/min/1.73 m2), mean±SD	59±22	59±23	60±22	57±19	0.39
BNP (pg/mL), median (IQR)	165 (63, 384)	190 (62, 389)	132 (66, 370)	155 (58, 378)	0.74
LVEF (%), mean±SD*	59±15	59±16	61±13	57±16	0.01
LAD (mm), mean±SD*	39±7	38±6	40±6	43±7	<0.0001
AP, n (%)*	157 (22)	96 (27)	39 (19)	22 (15)	0.007
VKA, n (%)*	85 (12)	15 (4)	26 (13)	44 (30)	<0.0001
DOAC, n (%)*	131 (18)	6 (2)	54 (27)	71 (48)	<0.0001
Mortality, n (%)	229 (32)	117 (33)	56 (28)	56 (38)	0.62

Numerical data are expressed as mean±standard deviation or median (interquartile; first quartile, third quartile). Categorical data are expressed as the percentage and number. *Statistical significance (P<0.05). AF, atrial fibrillation; AHRE, atrial high-rate episode; AP, antiplatelet agents; AVB, atrioventricular block; BNP, brain natriuretic peptide; BW, body weight; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; ICD, implantable cardioverter-defibrillator; LAD, left atrial diameter; LVEF, left ventricular ejection fraction; SSS, sick sinus syndrome; VKA, vitamin K antagonist.

Clinical Events

In the total population, 35 and 30 patients developed ischemic and major bleeding events, respectively. Figure 2 shows the distribution of the types of ischemic events (Figure 2A) and the major bleeding sites (Figure 2B). Although ischemic stroke was the most common ischemic event (29/35 patients, 83%), intracranial (13/30, 43%), followed by gastrointestinal (12/30, 40%) were the most common bleeding sites. The cumulative incidence of ischemic and major bleeding events in each group is shown in Figure 3. The incidence of ischemic events (Figure 3A) increased with increase in AHRE burden (17.2% [1.8/100 person-years] in ≥24 h, 9.1% [1.1/100 person-years] in ≥6 min to 24 h, and 5.6% [0.6/100 person-years] in <6 min groups). The incidence of major bleeding also increased with increase in AHRE burden (18.2% [1.4/100 person-years] in ≥24 h, 8.5% [1.0/100 person-years] in ≥6 min to 24 h, and 5.9% [0.5/100 person-years] in <6 min groups). The ≥24 h AHRE burden group had a significantly higher incidence of ischemic events (P=0.008) and major bleeding (P=0.04) compared to the <6 min group using a log-rank test. For a sensitivity analysis, the incidence was re-analyzed in patients who underwent the first procedure (N=564, Supplementary Figure 1). After re-analysis, the trends persisted for both the ischemic events (22.4% [2.2/100 person-years] in ≥24 h, 11.2% [1.2/100 person-years] in ≥6 min to 24 h, and 5.7% [0.7/100 person-years] in <6 min groups) and major bleeding (22.4% [1.7/100 person-years] in ≥24 h, 8.2% [1.1/100 person-years] in ≥6 min to 24 h, and 3.2% [0.4/100 person-years] in <6 min groups). The difference between the ≥24 h and <6 min AHRE burden groups in the incidence of ischemic events (P=0.002) and major bleeding (P=0.006) also remained the same. Regarding sensitivity analysis, the incidence was also re-analyzed in the population that excluded patients who were not previously diagnosed with AF (N=504, Supplementary Figure 2) had a similar result for ischemic events. Regarding ischemic events, the trends in which the incidence increased with the rising AHRE burden persisted, although it did not reach statistical significance (12.4% [1.4/100 person-years] in ≥24 h, 8.9% [1.0/100 person-years] in ≥6 min to 24 h, and 5.7% [0.6/100 person-years] in <6 min groups, P=0.21). However, incidence of major bleeding could not attest the original analyses (0.95% [0.46/100 person-years] in ≥24 h, 0.91% [1.03/100 person-years] in ≥6 min to 24 h, and 0.94% [0.55/100 person-years] in <6 min groups, P=0.7).

Figure 2.

Distribution of clinical events. (A) The pie chart shows the distribution of the types of ischemic events (pink: ischemic stroke, blue: systemic embolism, and green: transient ischemic attack). (B) The pie chart shows the distribution of the major bleeding sites (red: intracranial, blue: gastrointestinal, pink: chest, and gray: others).

Figure 3.

Cumulative incidence of clinical events. (A) The Kaplan-Meier curve shows a cumulative incidence of ischemic events in each group (black: AHRE burden ≥24 h, red: ≥6 min–24 h, and blue: <6 min). The incidence was significantly higher in the ≥24 h AHRE burden group than in the <6 min group (17.2% [1.8/100 person-years] vs. 5.6% [0.6/100 person-years], P=0.008). The asterisk indicates statistical significance. (B) The Kaplan-Meier curve shows a cumulative incidence of major bleeding in each group (black: AHRE burden of ≥24 h, red: ≥6 min–24 h, and blue: <6 min). The incidence was significantly higher in the ≥24 h AHRE burden group than in the <6 min group (18.2% [1.4/100 person-years] vs. 5.9% [0.5/100 person-years], P=0.04). The asterisk indicates statistical significance. AHRE, atrial high-rate episode

The clinical demographics of patients who developed these events are shown in Table 2 (A: ischemic events, B: major bleeding). Supplementary Table presents all details of the study population. Patients with ischemic events had a significantly higher mean age and CHADS₂ score. In addition, this group showed significant impairment in renal function and enlargement of the LAD. In contrast, patients with major bleeding had a higher mean age, although this was not statistically significant. The mean HAS-BLED score, prescribed antiplatelet agents, VKA, and DOAC, were similar between patients with and without major bleeding.

Table 2. Clinical Demographics of Patients With and Without Ischemic Events (A), Major Bleeding (B)

(A)	Total (n=710)	With ischemic events (n=35)	Without ischemic events (n=675)	P value
Age (years), mean±SD*	78±11	82±9	78±11	0.04
Female, n (%)	374 (53)	13 (37)	361 (53)	0.06
History of AF, n (%)*	206 (29)	16 (46)	190 (28)	0.03
BW (kg), mean±SD	53±11	53±9	53±11	0.62
ICD/CRT, n (%)	126 (18)	5 (14)	121 (18)	0.58
SSS, n (%)	266 (37)	17 (50)	249 (37)	0.16
AVB, n (%)	293 (41)	11 (32)	282 (42)	0.22
CHADS2, mean±SD*	2.4±1.1	2.8±1.1	2.4±1.1	0.046
CHA2DS2-VASc, mean±SD	4.0±1.4	4.4±1.2	3.9±1.5	0.11
AHRE burden of ≥24 h, n (%)*	139 (19)	15 (43)	124 (19)	<0.0001
eGFR (mL/min/1.73 m2), mean±SD*	59±22	51±19	59±22	0.02
BNP (pg/mL), median (IQR)	165 (63, 384)	156 (59, 649)	165 (64, 374)	0.85
LAD (mm), mean±SD*	39±7	43±9	40±7	0.01
AP, n (%)	157 (22)	9 (26)	148 (22)	0.59
VKA, n (%)	85 (12)	6 (17)	79 (12)	0.33
DOAC, n (%)	131 (18)	8 (23)	123 (18)	0.49
(B)	Total (n=710)	With major bleeding (n=30)	Without major bleeding (n=680)	P value
Age (years), mean±SD	78±11	81±13	78±11	0.08
Female, n (%)	374 (53)	13 (43)	361 (53)	0.29
History of AF, n (%)*	206 (29)	14 (47)	192 (28)	0.03
BW (kg), mean±SD	53±11	54±10	53±11	0.78
ICD/CRT, n (%)	126 (18)	6 (20)	120 (18)	0.74
SSS, n (%)	266 (37)	15 (50)	251 (37)	0.15
AVB, n (%)	293 (41)	12 (40)	281 (41)	0.88
HAS-BLED, mean±SD	1.9±1.0	2.0±1.1	1.9±1.0	0.51
AHRE burden of ≥24 h, n (%)*	139 (19)	11 (37)	128 (19)	0.02
eGFR (mL/min/1.73 m2), mean±SD	59±22	62±21	59±22	0.5
BNP (pg/mL), median (IQR)	165 (63, 384)	155 (46, 235)	166 (65, 385)	0.43
LAD (mm), mean±SD	39±7	41±8	40±7	0.42
AP, n (%)	157 (22)	7 (23)	150 (22)	0.86
VKA, n (%)	85 (12)	4 (13)	81 (12)	0.81
DOAC, n (%)	131 (18)	7 (23)	124 (18)	0.48

Numerical data are expressed as the mean±standard deviation or median (interquartile; first quartile, third quartile). Categorical data are expressed as the percentage and number. *Statistical significance (P<0.05). IQR, interquartile range; SD, standard deviation. Other abbreviations as in Table 1.

Univariate and Multivariate Analyses

The results of univariate and multivariate analyses (N=710) are summarized in Table 3. Following univariate analysis, age ≥85 years (HR: 3.8, 95% CI: 1.9–7.4, P=0.0001), history of AF (HR: 2.1, CI: 1.1–4.1, P=0.02), and an AHRE burden of ≥24 h (HR: 2.2, CI: 1.1–4.4, P<0.01) emerged as significant factors associated with ischemic events. Although female sex (HR: 0.51, CI: 0.25–1.01, P=0.054) and CHA₂DS₂-VASc score ≥4 (HR: 2.04, CI: 0.92–4.5, P=0.08) were also associated with ischemic events, they did not reach statistical significance. After multivariate analysis, age ≥85 years (HR: 3.9, CI: 2.03–7.7, P=0.0001) remained the only independent factor associated with ischemic events. As for major bleeding, age ≥85 years (HR: 2.9, CI: 1.4–6.2, P=0.003), and history of AF (HR: 2.2, CI: 1.1–4.5, P=0.03) were significant factors following univariate analysis. An AHRE burden of ≥24 h (HR: 1.9, CI: 0.9–4.03, P=0.08) indicated a tendency for the event; however, it did not reach statistical significance. Multivariate analysis found only age ≥85 years to be an independent factor associated with major bleeding (HR: 2.9, CI: 1.4–6.2, P=0.003).

Table 3. Identification of Factors Associated With Ischemic Events (A), Major Bleeding (B)

	Univariate Analysis			Multivariate Analysis
	HR	(95% CI)	P value	HR	(95% CI)	P value
(A)
Age ≥85 years*	3.8	1.9–7.4	0.0	3.9	2.0–7.7	0.0
Female	0.5	0.3–1.0	0.1	–	–	–
BW <50 kg	1.0	0.5–2.1	1.0	–	–	–
1st procedure	1.7	0.7–4.4	0.3	–	–	–
ICD/CRT	0.8	0.3–2.0	0.6	–	–	–
CHADS2 ≥3	1.7	0.9–3.4	0.1	–	–	–
CHA2DS2-VASc ≥4	2.0	0.9–4.5	0.1	–	–	–
History of AF	2.1	1.1–4.1	0.0	1.4	0.7–3.2	0.4
AHRE burden of ≥24 h	2.2	1.1–4.4	0.0	1.9	0.9–4.4	0.1
eGFR <30 mL/min/1.73 m2	1.0	0.3–4.3	1.0	–	–	–
LAD ≥40 mm	1.6	0.9–3.3	0.1	–	–	–
AP	1.2	0.6–2.7	0.5	–	–	–
VKA/DOAC	1.6	0.8–3.2	0.2	–	–	–
(B)
Age ≥85 years*	2.9	1.4–6.2	0.0	2.9	1.4–6.2	0.0
Female	0.7	0.3–1.4	0.3	–	–	–
BW <50 kg	0.9	0.4–1.9	0.8	–	–	–
1st procedure	1.1	0.5–2.7	0.8	–	–	–
ICD/CRT	1.1	0.5–2.9	0.7	–	–	–
HAS-BLED ≥3	1.0	0.4–2.3	1.0	–	–	–
History of AF	2.2	1.1–4.5	0.0	1.7	0.7–4.1	0.2
AHRE burden of ≥24 h	1.9	0.9–4.0	0.1	1.4	0.6–3.5	0.4
eGFR <30 mL/min/1.73 m2	0.6	0.1–4.1	0.6	–	–	–
LAD ≥40 mm	1.1	0.6–2.3	0.7	–	–	–
AP	1.1	0.5–2.7	0.7	–	–	–
VKA/DOAC	1.2	0.6–2.5	0.6	–	–	–

*Statistical significance after adjustment by multivariate analysis (P<0.05). HR, hazard ratio; CI, confidence interval. Other abbreviations as in Table 1.

Discussion

General Overview

The important findings of our study are as follows: the cumulative incidence of major bleeding as well as ischemic events increased in response to an increase in the duration of AHRE. Multivariate analyses showed that age ≥85 years was independently associated with both ischemic and major bleeding events.

Significance of AHRE

To the best of our knowledge, this is the first study to assess the association of the duration of AHRE with major bleeding as well as ischemic events. Although previous studies have shown the association of AHRE with ischemic events, very few have evaluated its association with both ischemic and major bleeding events.^4–8 Furthermore, studies on the importance of AHRE in the Asian population are limited. Kawakami et al elegantly described the association between ischemic stroke/SE and AHRE (>6 min) in a Japanese population.¹⁹ In their study, patients with a high thromboembolic risk (CHADS₂ score of >2) compared to those without it were at a significantly higher risk of ischemic events. However, data on the significance of AHRE after adjusting for confounding factors and duration of AHRE are yet to be obtained. In another study, Nakano et al nicely assessed the association between AHRE duration and embolic stroke in patients without a history of AF.²⁰ The authors reported an AHRE duration of 30 s as the optimal cut-off value to predict future embolic stroke. Furthermore, new onset of AF and LAD >40 mm were independent risk factors for embolic stroke after multivariate adjustment. However, there were limited patients with AHRE >24 h (2 patients, 3.6%) in the population. Even the previous studies evaluating the association between ischemic events and AHRE rarely investigated the significance of long duration AHRE in an Asian population.

A study in a non-Asian population showed an increase in the risk of ischemic events only in patients with AHRE >24 h.⁸ As for AF, recent studies have revealed that long-duration AF (i.e., persistent AF) increased the risk of stroke compared to short-duration AF (i.e., paroxysmal AF).^21–24 In agreement with the findings, our current data also show an increase in the risk of ischemic events with prolonged AHRE burden. Furthermore, our data suggested that patients with an AHRE burden of ≥96 h especially had the highest prevalence of both ischemic and bleeding risk (Supplementary Figure 3). However, the present population did not have enough patients with a very high duration of AHRE such as 24–48 h or 48–96 h to compare the cumulative incidence of clinical events based on the precise long duration of the AHRE burden. Further studies including a sufficient number of patients with a long duration of AHRE might help to stratify the risk for such patients.

We have also demonstrated an increase in major bleeding events with an increase in AHRE burden. There are several postulations to explain this. At first, our population included a large proportion of elderly patients and patients with relatively long-term follow ups. The multivariate analysis detected age ≥85 years as the most common factor associated with major bleeding and ischemic events. However, a regional registry-based study in Japan has reported that the risk of major bleeding was comparable in AF patients, both older and younger than 85 years.²⁵ This discrepancy might be due to the differences in the: (1) follow-up period; and (2) proportion of patients taking anticoagulants. The median follow-up period in our study was 4.5 years, which was longer than that in the registry-based study (mean 2.0 years²⁵). Furthermore, compared to the previous study,²⁵ our population included patients at a high risk of bleeding (i.e., group with AHRE duration ≥24 h) who were more often prescribed anticoagulants (78% vs. 49.9%²⁵).

As for previously published real-world-based studies for patients with AF, a post-marketing surveillance study of patients prescribed rivaroxaban revealed that the incidence of major bleeding as well as ischemic events was higher in patients aged ≥75 years than those aged <75 years.²⁶ Interestingly, another recent registry-based study in Japan, in which most of the participants were prescribed anticoagulants, showed that the risk of major bleeding (1.21/100 person/years) was comparable to that of ischemic events (1.47/100 person/years), even in a population where DOAC was predominantly chosen as the first-line anticoagulant.²⁷ Regarding our findings, we also demonstrate that major bleeding risk would be as high as the risk of ischemic events in a population that included a high proportion of patients receiving anticoagulation therapy. These findings are consistent with those of the two previous studies.^26,27 Therefore, it is important to monitor the bleeding risk in a current clinical setting wherein patients are routinely prescribed DOAC when clinicians initiate or continue anticoagulation therapy, especially for very elderly patients. Further studies on novel anticoagulation regimens suitable for very elderly patients (e.g., low-dose edoxaban²⁸) are warranted to address this issue.

Clinical Implications

Our data show an increase in major bleeding events as well as ischemic events, with increasing AHRE burden. A recent study of a non-Asian population, which investigated the effect of anticoagulation for patients with AHRE using propensity-score matching, showed that patients undergoing anticoagulation therapy had a lower risk of stroke than those who did not.²⁹ The latest European Society of Cardiology guidelines recommend initiating anticoagulation therapy for patients with long-duration AHRE (>24 h) and high thromboembolic risk, even if the diagnosis of AF is not confirmed.³⁰ However, our results suggest that patients with long-duration AHRE, especially the very elderly, are at an additional risk of major bleeding than those with short-duration AHRE. Therefore, close attention should be paid to the bleeding risk when clinicians consider anticoagulation therapy for patients with long AHRE. Furthermore, our results also suggest that the incidence of ischemic events would increase even if most patients with high AHRE burden were prescribed anticoagulation therapy. However, various factors would also be associated with the occurrence of ischemic events (e.g., low medication adherence). Clinicians should keep in mind that the high risk of ischemic events remain, even if patients with high AHRE burden were to undergo anticoagulation therapy.

Study Limitations

This study has some limitations. First, since the data were collected retrospectively, there might have been unmeasured variables related to clinical events. Second, being a single-center observational study, our population size was relatively small compared to previous studies.^4–7 Thus, future studies, including multiple institutions in Japan or other Asian countries, are warranted to validate our findings. Third, our population included patients with a history of AF who tend to be prescribed anticoagulation therapy. Our results could be affected by these patients; however, AF history was adjusted for in multivariate analysis. We also performed a re-analysis in the study population, which excluded patients who were previously diagnosed with AF. These results showed that the trends did not persist for major bleeding; however, the trend for increased ischemic events remained. Hence, it remains unclear whether major bleeding incidences would truly increase with increasing AHRE burden for patients not diagnosed with AF. Further studies in a population with larger patient numbers without AF history would answer this question.

Forth, we did not investigate the time when patients with AHRE developed clinical events. Previous studies have suggested that AHRE does not necessarily correspond with the development of ischemic events.^31,32 Hence, further studies assessing this relationship might help elucidate the relationship between AHRE and the ischemic events.

Finally, our population included the statistical difference in follow-up periods between 3 groups. Notably, the AHRE burden of the ≥24 h group had the longest follow-up period among the 3 groups. The difference in major bleeding incidences between groups might originate from the ≥24 h group, which included a relatively low number of patients that dropped out in the last few years of study (6–10 years). Further studies that will include patients with comparable follow-up periods are warranted to elucidate the association between longer AHRE and major bleeding.

Conclusions

Our findings suggest that patients with longer AHRE duration have higher numbers of major bleeding and ischemic events. Monitoring the bleeding risk is mandatory when clinicians initiate or continue anticoagulation therapy for very elderly patients with long-duration AHRE.

Acknowledgments

We thank the patients and their families for participating in this study. We also thank all the staff at the Shimane Prefectural Central Hospital for their contributions to this study.

Sources of Funding

This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

Disclosures

K.T., M. Yano are members of Circulation Journal’s Editorial Team. The other authors declare that they have no conflicts of interest. All authors take responsibility for all aspects of the reliability and unbiased presentation of the data and their interpretation.

IRB Information

This study was conducted in accordance with the tenets of the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation. The Institutional Review Boards of Shimane Prefectural Central Hospital (Churin R20-28) approved this study.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-1269

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