Effects of Longitudinal Changes in Anemia Status on Clinical Outcomes in Patients With Non-Valvular Atrial Fibrillation　― Analysis From the Hokuriku-Plus AF Registry ―

Abstract

Background: Anemia, a common comorbidity in older patients with heart failure (HF) and atrial fibrillation (AF), is associated with an increased risk of adverse events. This study evaluated the prognostic effects of longitudinal changes in anemia status on clinical outcomes in patients with AF.

Methods and Results: We prospectively evaluated data of 1,388 patients with AF from the Hokuriku-Plus AF Registry (1,010 men; mean [±SD] age 72.3±9.7 years) and recorded the incidence of death, HF, thromboembolism, and major bleeding. Of these patients, the 1,233 for whom hemoglobin levels were available at baseline and at the 1-year follow-up were further evaluated. Patients were categorized into 3 groups based on longitudinal changes in 1-year anemia status: Group 1, AF without anemia; Group 2, AF with improved anemia; and Group 3, AF with sustained or new-onset anemia. Over the 1–5 years of follow up, the incidences of death, HF, thromboembolism, and major bleeding were significantly higher among patients with than without anemia. In addition, the incidence of death or HF was significantly higher in Group 3 than in Groups 1 and 2. Multivariate analysis revealed no anemia or improvement in anemia in 1 year as an independent predictor for a favorable prognosis for cardiovascular death and HF.

Conclusions: Recovery from anemia may be associated with a favorable clinical course of AF.

Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with a wide range of adverse events, including cardiovascular (CV) death, heart failure (HF),¹ worsening renal function,² sudden cardiac death,^3,4 and thromboembolism.⁵ Owing to increased life expectancy and a rapidly growing older adult population, the number of patients with AF is expected to rise rapidly worldwide.^6,7 Anemia is a common comorbidity in the older adult population,⁸ as well as in those with HF⁹ and AF.¹⁰ Several studies have reported that the presence of anemia is associated with an increased risk of adverse events, including death, bleeding, and HF in the AF population.^10–13 The adverse effects of anemia are already well known in patients with HF.¹⁴ Current guidelines for the management of HF from the European Society of Cardiology recommend the routine screening and treatment of anemia to improve exercise capacity and quality of life and to reduce hospitalization in these patients.^15,16 However, despite the increasing prevalence of AF and anemia in the aging population, limited studies have focused on the potential effects of the presence of anemia and longitudinal changes in anemia status on the clinical course of AF in the Asian population. Accordingly, data on whether anemia may be an important target for routine screening and treatment to improve the clinical course in patients with AF remain scarce.

This study aimed to evaluate the prognostic effects of longitudinal changes in anemia status on clinical outcomes in patients with AF who were a part of the Japanese multicenter prospective cohort, the Hokuriku-Plus AF Registry.^17–20

Methods

Study Population, Design, and Definition of Anemia

This study adhered to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee for Medical Research of Kanazawa University Graduate School of Medical Science (1394-4). All participants provided written informed consent.

The Hokuriku-Plus AF Registry is a multicenter, population-based, prospective cohort study that has been described in detail elsewhere.¹⁷ A flowchart of patient selection for the present study is shown in Figure 1. Briefly, 1,396 patients with non-valvular AF (NVAF), aged 33–94 years, were recruited from 19 institutions in the Hokuriku and Yokohama areas. Baseline enrollment was performed between January 2013 and May 2014, and follow-up examinations were conducted annually from baseline up to 5 years. Of the 1,396 patients with NVAF in the Hokuriku-Plus AF Registry, the 1,388 patients for whom baseline hemoglobin (Hb) data were available were included in the present study. Anemia was defined according to the World Health Organization criteria as Hb levels ≤13.0 g/dL in men and ≤12.0 g/dL in women.²¹ Patients with anemia were categorized into 3 groups based on Hb levels at baseline as follows: mild anemia, Hb 11.0 to <13.0 g/dL for men and 11.0 to <12.0 g/dL for women; moderate anemia, Hb 8.0 to <11.0 g/dL; and severe anemia, Hb <8.0 g/dL.

Figure 1.

Flowchart of patient selection for this study. AF, atrial fibrillation.

Further, we evaluated the effects of longitudinal changes in anemia status on clinical outcomes over a 1-year follow-up. To this end, we excluded 121 patients with NVAF who did not have data on Hb levels at the 1-year follow-up. In addition, to eliminate the effects of adverse events on anemia status, we excluded another 34 patients who experienced thromboembolism, major bleeding, or HF within the 1-year follow-up period. Thus, the effects of longitudinal changes in anemia status on the clinical course over the 1-year follow-up period were evaluated the 1,233 patients with NVAF. These patients were categorized into 3 groups based on the presence or absence of anemia at baseline and at the 1-year follow-up as follows: Group 1, no anemia at either baseline or the 1-year follow-up; Group 2, anemia at baseline but not at the 1-year follow-up; and Group 3, either anemia at baseline and the 1-year follow-up or no anemia at baseline but anemia at the 1-year follow-up. Finally, we evaluated longitudinal changes in anemia status and clinical outcomes in 94 patients with moderate or severe anemia at baseline.

Risk Factor Definitions and Examination Data

We recorded CHADS₂,²² CHA₂DS₂-VASc,²³ and HAS-BLED²⁴ scores at baseline as indicators of the risk of stroke (CHADS₂, CHA₂DS₂-VASc) and bleeding (HAS-BLED). The prothrombin time-international normalized ratio (PT-INR), as well as the time in therapeutic range (TTR), were measured as described previously to evaluate the intensity of anticoagulation by warfarin.²⁵ The optimal intensity of anticoagulation is defined as a PT-INR of 1.6–2.6 for older (age ≥70 years) patients and 2.0–3.0 for younger (age <70 years) patients.²⁶

To evaluate the use of direct oral anticoagulants (DOACs), we defined “off-label use of DOAC” as the underdosing or overdosing of DOACs. DOAC underdosing was defined as inappropriately low dosing, which corresponded to the administration of low-dose DOACs despite the recommendation for a standard dose. DOAC overdosing was defined as inappropriately standard dosing, which corresponded to the administration of standard-dose DOACs despite the recommendation for a low dose.

Echocardiographic data including left atrial diameter and left ventricular ejection fraction.

Outcomes

The endpoint of this analysis was the occurrence of adverse events, including all-cause death, CV or non-CV death, thromboembolism, major bleeding, and HF. CV death included death from causes such as HF, vascular disease, or sudden cardiac death. Non-CV death included death from causes such as cancer, respiratory disease, and lethal bleeding. Thromboembolism included ischemic or hemorrhagic stroke, transient ischemic attack, and systemic embolism. Stroke was defined as the sudden onset of focal deficits lasting >24 h and was further categorized as ischemic or hemorrhagic. Systemic embolism was defined as an acute vascular occlusion outside the brain. Major bleeding events included intracranial hemorrhage, bleeding requiring transfusion, and bleeding with a reduction in the Hb level of >2 g/dL. HF was defined as the onset of acute HF requiring additional medical therapy or hospitalization for treatment.

Statistical Analysis

Continuous variables are presented as the mean±SD and categorical variables are presented as percentages. Continuous and categorical variables were compared among the 3 groups using one-way analysis of variance and Fisher’s exact test, respectively. Adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for each variable associated with adverse events were calculated using the Cox proportional hazards model. To investigate the significance of differences between groups in the cumulative ratio of adverse events, the occurrence of adverse events was presented using Kaplan-Meier cumulative survival curves and compared using log-rank tests. Two-sided P<0.05 was considered statistically significant.

All statistical analyses were performed using JMP Pro version 14 (SAS Institute, Cary, NC, USA) or EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.²⁷

Results

Baseline Characteristics and Outcomes

Among the 1,396 patients with NVAF who were a part of the Hokuriku-Plus AF Registry, serum Hb levels at baseline were available for 1,388 (99.4%). In the present study, we prospectively analyzed the data of 1,388 patients with NVAF (1,010 men; mean age 72.3±9.7 years) for a median of 5.0 years (interquartile range 3.5–5.3 years) and evaluated the incidence of adverse events, including all-cause death, HF, thromboembolism, and major bleeding.

First, we investigated the clinical impact of anemia at baseline on patients with AF. The baseline characteristics of the entire cohort and NVAF patients with no, mild, and moderate or severe (M/S) anemia separately are presented in Table 1. As expected, many significant differences were observed between the 3 anemia groups. Compared with patients without anemia, those with anemia were older, had a lower body mass index, had a higher incidence of comorbidities, and exhibited increased intake of antiplatelet drugs. In contrast, the rates of anticoagulation therapy, including warfarin or DOACs, were similar among the 3 groups. Compared with patients in the no and mild anemia groups, those in the M/S anemia group had a tendency for lower TTR, indicating poor warfarin control, and a higher rate of the off-label use of DOACs. During a median follow-up period of 5 years, all-cause death occurred in 163 patients (2.7/100 person-years), CV death occurred in 56 patients (0.9/100 person-years), non-CV death occurred in 107 patients (1.8/100 person-years), HF occurred in 192 patients (3.2/100 person-years), thromboembolism occurred in 78 patients (1.3/100 person-years), and major bleeding in occurred 109 patients (1.8/100 person-years). Of the 56 patients who died from CV-related causes, 31 (55%) died due to HF, 20 (36%) died due to sudden cardiac death, and 5 (9%) died due to vascular disease. Of the 107 patients who died from non-CV-related causes, 46 (43%) died due to cancer, 32 (30%) died due to respiratory disease, 15 (14%) died due to lethal bleeding, and 14 (13%) died due to other causes. The incidences of all-cause death, HF, thromboembolism, and major bleeding in the 3 groups (no, mild, and M/S anemia) are shown in Figure 2. The incidences of all-cause death and HF were higher in NVAF patients with than without anemia. Notably, the incidence of all-cause death and HF increased with the severity of anemia. In contrast, the incidence of thromboembolism and major bleeding was higher in the M/S anemia group than in the mild or no anemia groups.

Table 1.

Baseline Characteristics of the Entire AF Cohort and According to Anemia Status

	All cohort (n=1,388)	No anemia (n=1,020)	Mild anemia (n=250)	M/S anemia (n=118)	P value
Age (years)	72.3±9.7	70.7±9.7	75.8±8.5	79.4±6.6	<0.0001
Male sex	1,010 (72.8)	745 (73.0)	199 (79.6)	66 (55.9)	<0.0001
Heart rate (beats/min)	74.3±14.6	74.4±14.8	73.5±14.3	75.0±14.5	0.59
SBP (mmHg)	125.4±17.4	126.0±16.9	124.0±18.7	123.5±18.9	0.11
BMI (kg/m2)	23.7±3.7	24.1±3.6	22.6±3.7	22.2±4.0	<0.0001
Persistent or permanent AF	874 (63.0)	657 (64.4)	146 (58.4)	71 (60.1)	0.17
History of HF	440 (31.7)	271 (26.6)	101 (40.4)	68 (57.6)	<0.0001
Hypertension	875 (63.0)	643 (63.0)	149 (59.6)	83 (70.3)	0.13
Diabetes	381 (27.5)	278 (27.3)	69 (27.6)	34 (28.8)	0.93
Prior stroke or TIA	183 (13.2)	115 (11.3)	50 (20.0)	18 (15.3)	0.002
Vascular disease	300 (21.6)	193 (18.9)	71 (28.4)	36 (30.5)	0.0003
CHADS2 score	1.93±1.30	1.77±1.26	2.26±1.33	2.63±1.25	<0.0001
CHA2DS2-VASc score	3.24±1.74	3.00±1.71	3.69±1.65	4.39±1.50	<0.0001
Prior bleeding	29 (2.1)	16 (1.6)	8 (3.2)	5 (4.2)	0.09
HAS-BLED score	1.80±1.07	1.45±0.91	2.72±0.85	2.86±0.89	<0.0001
Hemoglobin (g/dL)	13.6±1.8	14.4±1.2	12.0±0.6	9.9±0.9	<0.0001
Creatinine (mg/dL)	0.97±0.64	0.88±0.34	1.09±0.86	1.43±1.38	<0.0001
Cancer	126 (9.1)	69 (6.8)	31 (12.4)	26 (22.0)	<0.0001
Cardiomyopathy	122 (8.8)	90 (8.8)	20 (8.0)	12 (10.2)	0.79
Total cholesterol (mg/dL)	180±34	185±33	170±32	157±34	<0.0001
BNP (pg/mL)	167±249	145±197	196±287	275±428	<0.0001
LA diameter (mm)	44.1±8.4	43.8±8.0	44.5±9.5	46.7±8.9	0.003
LVEF (%)	71.0±11.7	71.2±11.6	69.9±12.9	71.3±10.3	0.31
Any OAC	1,192 (85.9)	873 (85.6)	216 (86.4)	103 (87.3)	0.85
Warfarin	748 (53.9)	550 (53.9)	129 (51.6)	69 (58.5)	0.47
DOAC	444 (32.0)	323 (31.7)	87 (34.8)	34 (28.8)	0.47
TTR (warfarin users; %)	71.4±19.8	72.0±19.4	71.8±21.3	65.8±19.2	0.06
Off-label use of DOAC	83 (6.0)	53 (5.2)	17 (6.8)	13 (11.0)	0.06
Over dose of DOAC	17 (1.2)	11 (1.1)	5 (2.0)	1 (0.8)	0.49
Under dose of DOAC	66 (4.8)	42 (4.1)	12 (4.8)	12 (10.2)	0.03
Post PCI	119 (8.6)	82 (8.0)	25 (10.0)	12 (10.2)	0.51
Antiplatelet drugs	366 (26.4)	243 (23.8)	79 (31.6)	44 (37.3)	0.001
Catheter ablation	98 (7.1)	79 (7.8)	15 (6.0)	4 (3.4)	0.13
Anti-arrhythmic drugs (Vaughan Williams classification)	816 (58.8)	603 (59.1)	147 (58.8)	66 (55.9)	0.80
Class I	300 (21.6)	228 (22.4)	56 (22.4)	16 (13.6)	0.07
Class II	429 (30.9)	310 (30.4)	74 (29.6)	45 (38.1)	0.21
Class III	33 (2.4)	24 (2.4)	7 (2.8)	2 (1.7)	0.79
Class IV	264 (19.0)	204 (20.0)	47 (18.8)	13 (11.0)	0.05

Unless indicated otherwise, data are given as the mean±SD or n (%). AF, atrial fibrillation; BMI, body mass index; BNP, B-type natriuretic peptide; DOAC, direct oral anticoagulant; HF, heart failure; LA, left atrium; LVEF, left ventricular ejection fraction; M/S, moderate or severe; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; TIA, transient ischemic attack; TTR, time in therapeutic range.

Figure 2.

Kaplan-Meier analysis of the incidence of (A) all-cause death, (B) heart failure, (C) thromboembolism, and (D) and major bleeding in patients without anemia, with mild anemia, and moderate or severe anemia at baseline. CI, confidence interval; HR, hazard ratio; M/S, moderate or severe.

Longitudinal Changes in Anemia Status and Outcomes After 1-Year Follow-up

We evaluated the clinical impacts of longitudinal changes in anemia status in patients with AF. Of the 1,233 patients who met the eligibility criteria for this analysis, 815 (66.1%) maintained no anemia status during the first year of follow up (Group 1), 71 (5.8%) had recovered from anemia at baseline at the 1-year follow-up (Group 2), and 347 (28.1%) showed sustained or new-onset anemia at the 1-year follow-up (Group 3). Patient characteristics at the 1-year follow-up for these 3 groups are presented in Table 2. There were several differences among these 3 groups (age, body mass index, comorbidities, Hb level, and renal function) at the 1-year follow up. The change in Hb level over the 1-year follow-up was −0.1±0.8 g/dL in Group 1, +1.5±1.3 g/dL in Group 2, and −0.7±1.3 g/dL in Group 3. Anticoagulation therapy during the 1-year follow-up period was similar among the 3 groups.

Table 2.

Patient Characteristics at Baseline and 1 Year According to Changes in Anemia Status During the First Year of Follow up

	Group 1 (n=815)	Group 2 (n=71)	Group 3 (n=347)	P value
Age (years)	70.9±9.6	74.9±8.7	78.1±7.5	<0.0001
Male sex	601 (73.7)	53 (74.7)	238 (68.6)	0.18
BMI at 1 year (kg/m2)	24.2±3.9	22.3±3.1	22.6±3.7	<0.0001
Persistent or permanent AF	505 (62.0)	35 (49.3)	208 (59.9)	0.11
History of HF	193 (23.7)	24 (33.8)	170 (49.0)	<0.0001
Hypertension	518 (63.6)	39 (54.9)	231 (66.5)	0.17
Diabetes	219 (26.9)	18 (25.4)	103 (29.7)	0.56
Prior stroke or TIA	94 (11.5)	12 (16.9)	56 (16.1)	0.07
Vascular disease	145 (17.8)	14 (19.7)	101 (29.1)	0.0001
CHADS2 score	1.68±1.22	1.99±1.39	2.42±1.22	<0.0001
CHA2DS2-VASc score	2.92±1.71	3.43±1.75	4.03±1.60	<0.0001
Hemoglobin (g/dL)
At baseline	14.6±1.2	12.1±1.1	11.8±1.4	<0.0001
At 1 year	14.3±1.2	13.6±0.9	11.2±1.2	<0.0001
Creatinine (mg/dL)
At baseline	0.86±0.34	0.98±0.79	1.15±0.93	<0.0001
At 1 year	0.88±0.22	0.88±0.26	1.19±0.86	<0.0001
Cancer	63 (7.7)	13 (18.3)	64 (18.4)	<0.0001
Cardiomyopathy	73 (9.0)	7 (9.9)	23 (6.6)	0.36
Total cholesterol (mg/dL)	180±32	181±31	162±33	<0.0001
During the 1-year follow-up
Warfarin use	393 (48.2)	26 (36.6)	161 (46.4)	0.15
DOAC use	266 (32.6)	31 (43.7)	110 (31.7)	0.16
Change from warfarin to DOAC	49 (6.0)	6 (8.5)	30 (8.7)	0.24
Change from DOAC to warfarin	0 (0.0)	0 (0.0)	0 (0.0)	1.00
Discontinuation of OAC	7 (0.9)	1 (1.4)	5 (1.4)	0.66
No OAC	100 (12.2)	7 (9.9)	41 (11.8)	0.82
PCI	11 (1.4)	0 (0.0)	8 (2.3)	0.17
Antiplatelet drugs	175 (21.5)	12 (16.9)	100 (28.8)	0.01
Catheter ablation for AF during the 1-year follow-up	21 (2.6)	0 (0.0)	9 (2.6)	0.16
Anti-arrhythmic drugs (Vaughan Williams classification)	520 (63.8)	45 (63.4)	214 (61.7)	0.48
Class I	189 (23.2)	21 (29.6)	61 (17.6)	0.03
Class II	243 (29.8)	21 (29.6)	110 (31.7)	0.81
Class III	18 (2.2)	1 (1.4)	11 (3.2)	0.53
Class IV	173 (21.2)	9 (12.7)	60 (17.3)	0.08

Unless indicated otherwise, data are given as the mean±SD or n (%). Group 1, no anemia during the 1 year of follow up; Group 2, recovery from anemia at baseline over the 1-year follow-up; Group 3, sustained or new-onset anemia at the 1-year follow-up. Other abbreviations as in Table 1.

From the first to the last year of follow up, all-cause death occurred in 127 patients (2.9/100 person-years), CV death occurred in 41 patients (0.9/100 person-years), non-CV death occurred in 86 patients (1.9/100 person-years), and HF occurred in 171 patients (3.8/100 person-years). Of the 41 patients who died from CV-related causes, 26 (63.4%) died due to HF, 10 (24.4%) died due to sudden cardiac death, and 5 (12.2%) died due to vascular disease. Of the 86 patients who died from non-CV-related causes, 33 (38%) died due to cancer, 28 (33%) died due to a respiratory disease, 12 (14%) died due to lethal bleeding, and 13 (15%) died due to other causes. Compared with Group 1, Group 3 had a higher incidence of all-cause death, CV/non-CV death, and HF. There were no significant differences in the incidence of all-cause death, CV/non-CV death, and HF between Groups 1 and 2 (Figure 3). The incidence of CV death and HF was significantly lower in Group 2 than in Group 3.

Figure 3.

Kaplan-Meier analysis of the incidence of (A) all-cause death, (B) cardiovascular death, (C) non-cardiovascular death, and (D) heart failure beyond the 1-year follow up according to changes in anemia status during the first year of follow up. CI, confidence interval; Group 1, no anemia during the 1 year of follow up; Group 2, recovery from anemia at baseline over the 1-year follow-up; Group 3, sustained or new-onset anemia at the 1-year follow-up; HR, hazard ratio.

We used a Cox hazard model to identify predictors of CV death, non-CV death, and HF after adjusting for confounders in the first year of follow up. The Cox hazard model indicated that no anemia during the 1-year follow-up or recovery from baseline anemia at the 1-year follow-up were independent predictors of a decreased incidence of CV death (HR 0.49; 95% CI 0.23–1.00; P=0.04) and HF (HR 0.63; 95% CI 0.45–0.88; P=0.007; Tables 3,4). Conversely, advanced age, concomitant cancer, and renal dysfunction were independent predictors for the occurrence of non-CV death (Supplementary Table 1).

Table 3.

Cox Hazard Model for Predicting Cardiovascular Death

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age at the 1-year follow-up	1.09 (1.05–1.14)	<0.0001	1.06 (1.01–1.11)	0.008
Male sex	0.84 (0.44–1.68)	0.62
Persistent or permanent AF	1.33 (0.70–2.65)	0.39
History of HF	12.4 (5.85–30.6)	<0.0001	7.01 (3.16–17.7)	<0.0001
Hypertension	1.42 (0.74–2.89)	0.29
Diabetes	1.24 (0.62–2.35)	0.53
Prior stroke or TIA	0.98 (0.57–1.49)	0.92
Vascular disease	3.58 (1.92–6.61)	0.0001	2.02 (1.04–3.87)	0.04
Cardiomyopathy	2.48 (1.14–5.37)	0.02	1.97 (0.83–4.17)	0.12
No anemia or recovery from anemia at the 1-year follow-up	0.17 (0.10–0.32)	<0.0001	0.49 (0.23–1.00)	0.04
Serum creatinine level at the 1-year follow-up	1.82 (1.50–2.10)	<0.0001	1.45 (1.14–1.74)	0.005
Catheter ablation for AF during the 1-year follow-up	0.29 (0.02–1.37)	0.14
Anti-arrhythmic drugs	1.09 (0.59–2.08)	0.79

CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Table 4.

Cox Hazard Model for Predicting HF

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age at the 1-year follow-up	1.09 (1.07–1.11)	<0.0001	1.07 (1.05–1.10)	<0.0001
Male sex	0.72 (0.53–0.99)	0.04	0.96 (0.69–1.34)	0.82
Persistent or permanent AF	1.36 (0.98–1.89)	0.06
History of HF	3.54 (2.62–4.81)	<0.0001	2.25 (1.62–3.11)	<0.0001
Hypertension	1.07 (0.79–1.47)	0.66
Diabetes	1.01 (0.72–1.40)	0.95
Prior stroke or TIA	1.11 (0.89–1.36)	0.32
Vascular disease	1.32 (0.92–1.86)	0.12
No anemia or recovery from anemia at the 1-year follow-up	0.31 (0.23–0.42)	<0.0001	0.63 (0.45–0.88)	0.007
Serum creatinine level at the 1-year follow-up	1.77 (1.53–1.99)	<0.0001	1.48 (1.24–1.76)	0.001
Cardiomyopathy	2.78 (1.88–4.00)	<0.0001	2.87 (1.92–4.30)	<0.0001
Catheter ablation for AF during the 1-year follow-up	0.64 (0.30–1.19)	0.17
Anti-arrhythmic drugs	0.94 (0.69–1.28)	0.71

Abbreviations as in Tables 1,3.

Longitudinal Changes in Anemia Status and Outcomes in AF With M/S Anemia

Finally, we evaluated longitudinal changes in anemia status and outcomes in the M/S anemia group. Of the 94 patients with M/S anemia at baseline, 6 had recovered from anemia at the 1-year follow-up, 22 had mild anemia at the 1-year follow-up, and 66 still had M/S anemia at the1-year follow-up. As shown in the Supplementary Figure, there were no significant differences in the incidence of CV death or HF between patients with sustained M/S anemia at the 1-year follow-up and those in whom the anemia had improved to mild. No adverse events were recorded in the 6 patients who recovered from M/S anemia at baseline.

It is possible that the improved prognosis may not be attributable solely to the improvement in the degree of anemia. Therefore, we evaluated the characteristics of these 3 groups at the 1-year follow-up (Supplementary Table 2); there were no significant differences in patient characteristics, except for Hb levels, among the 3 groups. However, there was a tendency for serum creatinine concentrations to be higher in the groups with mild and sustained M/S anemia at 1 year compared with the group that had recovered from anemia at 1 year. In addition, concomitant cardiomyopathy tended to be more frequently seen in the recovered and mild anemia groups than in the sustained M/S anemia group.

Discussion

Main Findings

The findings of this Japanese multicenter prospective study including an AF cohort are as follows: (1) AF patients with anemia, especially M/S anemia, have a higher risk of experiencing adverse outcomes than AF patients without anemia; (2) AF patients with anemia at baseline but not at the 1-year follow up have a lower incidence of CV death and HF than AF patients with sustained or new-onset anemia; and (3) maintenance of no anemia status or recovery from anemia were identified an independent predictors of reduced incidence of CV death or HF in patients with AF.

Anemia and Clinical Outcomes in Patients With AF

Anemia is a common comorbidity associated with increased mortality and morbidity in various diseases, such as HF,²⁸ ischemic heart disease,²⁹ and cancer.³⁰ In addition, anemia is associated with an increased risk of bleeding among patients with AF,^31,32 and is therefore included in most bleeding scores.³³ Previous reports from a Japanese AF cohort showed that the presence of anemia was associated with the future risk of mortality,^12,13 bleeding,³⁴ and HF.¹¹ These results are consistent with our findings. In our study, the incidence of thromboembolism was significantly higher in the M/S anemia group than in the other 2 anemia groups. At baseline, the M/S anemia group had high CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores. In contrast, there was a tendency for lower TTR among warfarin users and a tendency for a higher rate of off-label DOACs use, especially under-dosing, in the M/S anemia group compared with in the other 2 anemia groups. Concerns about bleeding events in individuals with M/S anemia may affect suboptimal anticoagulation and lead to a higher incidence of thromboembolism in the M/S anemia group. These findings suggest that in patients with M/S anemia with both thromboembolic and bleeding risk, the prescription of a proper dose and close monitoring of anticoagulant therapy are needed.

Anemia is associated with increased cardiac output, workload, and ventricular hypertrophy,³⁵ and has a direct adverse effect on CV hemodynamics.³⁶ Because both anemia and AF have adverse effects on cardiac function and hemodynamics, the incidence of HF increased in accordance with the severity of anemia in our cohort. A previous large AF cohort study showed that the most common non-fatal adverse event in the AF population is HF, rather than stroke or bleeding.⁴ In addition, the onset of HF was a major cause of CV death in an AF population.⁴ In our study, more than half the patients with CV-related deaths died of HF, and anemia was one of the reasons for the high incidence of CV deaths in patients with AF. In contrast, sudden cardiac death accounted for 36% of CV deaths. Previously, a nationwide cohort study in South Korea showed a relationship between anemia and the risk of sudden cardiac death due to a prolonged QTc interval.³⁷ Patients with AF who are anemic should be carefully monitored for the incidence of sudden cardiac death.

Longitudinal Changes in Anemia Status and Clinical Outcomes in Patients With AF

Anemia itself is an independent indicator of poor prognosis in various diseases, although it can be modified by treatment or various physical or comorbid conditions. In the present study, we evaluated the incidence of death and HF based on longitudinal changes in anemia status. A lower incidence of adverse events was observed in the groups with no anemia and recovered from anemia at 1 year than in the groups with sustained or new-onset anemia at 1 year. Even after adjusting for other confounders, favorable management of anemia in patients with AF was associated with a reduced incidence of CV death or HF. Similar results have been reported previously in cohort studies on HF³⁸ and myocardial infarction.³⁹ Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN)⁴⁰ trial and a recent meta-analysis⁴¹ reported that intravenous iron therapy in patients with HF and concomitant iron deficiency-induced anemia reduces the risk of HF. These results suggest a possible effect of the treatment of anemia on the prognosis of these patients. In addition, a subanalysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial evaluated the change in anemic status in an AF cohort and reported that the incidence of all-cause death and myocardial infarction was lower in the group with transient anemia or no anemia.³¹ The results of our study add to the findings of reduced CV death and HF in patients without anemia and in those who have recovered from anemia. The Japanese Circulation Society guidelines recommend optimal pharmacological therapy to improve the prognosis of HF.⁴² Recently, Oshima et al.⁴³ reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are recommended for the treatment of HF with reduced ejection fraction (HFrEF),⁴² reduced the incidence of anemia. SGLT2 inhibitors may be a therapeutic choice for the treatment of AF with concomitant HFrEF and anemia. Anemia is a modifiable risk factor for cardiac diseases, including HF, ischemic heart disease, and AF. Therefore, proper management of anemia, such as maintaining a no-anemia status or recovery from anemia, could improve the prognosis of patients with AF.

Longitudinal Changes in Anemia Status in Patients With AF and M/S Anemia

In the present study, we evaluated longitudinal changes in anemia status in patients with M/S anemia at baseline. As shown in the Supplementary Figure, the incidence of CV death or HF was similar between the group with sustained M/S anemia at 1 year and the group that transitioned from M/S to mild anemia. Differences in characteristics at the 1-year follow-up among the 3 anemia groups, including those relating to renal function or underlying heart disease, especially cardiomyopathy, may affect these results; however, there were no statistically significant differences in characteristics at 1-year follow up. In terms of the management of M/S anemia in AF, it is important to eliminate residual anemia to improve the prognosis of patients with AF.

Study Limitations

Our study has some limitations. First, this study included a relatively small sample size compared with other AF studies. Second, our study did not evaluate the detailed etiology of anemia, which may have affected the clinical course of AF in our study population. Third, because detailed data on treatment for anemia were not available, we were unable to explore the association between the results and the treatment of anemia. Fourth, the longitudinal changes in anemia status from the first to the last year of follow up were not assessed in this study. Fifth, in our study, catheter ablation was performed at baseline in only 7% of patients with AF, and we could not evaluate the effect of catheter ablation performed during the follow-up period. Finally, we did not fully assess the medical therapy for HF, which may have affected the incidence of CV events.

Conclusions

In a real-world cohort of Japanese patients with AF, anemia was associated with an increased risk of adverse outcomes. Complete recovery from anemia was associated with a favorable clinical course in patients with AF.

Acknowledgments

The authors thank all the centers that participated in this study and all the patients who provided consent for the use of their data. The institutions and physicians participating in the Hokuriku-Plus AF Registry are listed in the Supplementary Appendix. The authors thank Editage (www.editage.com) for help with English language editing.

Sources of Funding

The Hokuriku-Plus AF Registry was supported, in part, by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP17ek0210082 (K.H.) and a Grant-in-Aid for Early-Career Scientists under Grant Number 21K16052 (T.T.).

Disclosures

The authors declare that they have no conflicts of interest.

IRB Information

This study adhered to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee for Medical Research of Kanazawa University Graduate School of Medical Science (1394-4). All participants provided written informed consent.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0132

References

• 1.   Wang TJ, Larson MG, Levy D, D’Agostino RB, Murabito JM, Kannel WB, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: The Framingham Heart Study. Circulation 2003; 107: 2920–2925.
• 2.   Kuronuma K, Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Oiwa K, et al. Worsening renal function, adverse clinical events and major determinants for changes of renal function in patients with atrial fibrillation: A Japanese multicenter registry substudy. Curr Med Res Opin 2019; 35: 2007–2013.
• 3.   Bassand JP, Accetta G, Camm AJ, Cools F, Fitzmaurice DA, Fox KA, et al. Two-year outcomes of patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF. Eur Heart J 2016; 37: 2882–2889.
• 4.   An Y, Ogawa H, Yamashita Y, Ishii M, Iguchi M, Masunaga N, et al. Causes of death in Japanese patients with atrial fibrillation: The Fushimi Atrial Fibrillation Registry. Eur Heart J Qual Care Clin Outcomes 2019; 5: 35–42.
• 5.   Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–988.
• 6.   Wong CX, Brown A, Tse HF, Albert CM, Kalman JM, Marwick TH, et al. Epidemiology of atrial fibrillation: The Australian and Asia-Pacific perspective. Heart Lung Circ 2017; 26: 870–879.
• 7.   Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013; 34: 2746–2751.
• 8.   Gaskell H, Derry S, Moore RA, McQuay HJ. Prevalence of anaemia in older persons: Systematic review. BMC Geriatr 2008; 8: 1.
• 9.   O’Meara E, Rouleau JL, White M, Roy K, Blondeau L, Ducharme A, et al. Heart failure with anemia: Novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes. Circ Heart Fail 2014; 7: 773–781.
• 10.   Tu SJ, Hanna-Rivero N, Elliott AD, Clarke N, Huang S, Pitman BM, et al. Associations of anemia with stroke, bleeding, and mortality in atrial fibrillation: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2021; 32: 686–694.
• 11.   An Y, Ogawa H, Esato M, Ishii M, Iguchi M, Masunaga N, et al. Cardiovascular events and mortality in patients with atrial fibrillation and anemia (from the Fushimi AF Registry). Am J Cardiol 2020; 134: 74–82.
• 12.   Kodani E, Inoue H, Atarashi H, Okumura K, Yamashita T, Origasa H. Impact of hemoglobin concentration and platelet count on outcomes of patients with non-valvular atrial fibrillation: A subanalysis of the J-RHYTHM Registry. Int J Cardiol 2020; 302: 81–87.
• 13.   Kuronuma K, Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Oiwa K, et al. Different determinants of vascular and nonvascular deaths in patients with atrial fibrillation: A SAKURA AF Registry substudy. J Cardiol 2019; 73: 210–217.
• 14.   Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oleśkowska-Florek W, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J 2014; 35: 2468–2476.
• 15.   McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726.
• 16.   McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023; 44: 3627–3639.
• 17.   Hayashi K, Tsuda T, Nomura A, Fujino N, Nohara A, Sakata K, et al. Impact of B-type natriuretic peptide level on risk stratification of thromboembolism and death in patients with nonvalvular atrial fibrillation: The Hokuriku-Plus AF Registry. Circ J 2018; 82: 1271–1278.
• 18.   Tsuda T, Hayashi K, Fujino N, Konno T, Tada H, Nomura A, et al. Effect of hypertrophic cardiomyopathy on the prediction of thromboembolism in patients with nonvalvular atrial fibrillation. Heart Rhythm 2019; 16: 829–837.
• 19.   Yamagishi M, Tsuda T, Kato T, Furusho H, Hayashi K. Cost-effectiveness for prevention of thromboembolism by anticoagulants in non-valvular atrial fibrillation: Additional analysis from the Hokuriku-Plus AF Registry. Heart Vessels 2019; 34: 1024–1030.
• 20.   Tsuda T, Hayashi K, Kato T, Usuda K, Kusayama T, Nomura A, et al. Clinical characteristics, outcomes, and risk factors for adverse events in elderly and non-elderly Japanese patients with non-valvular atrial fibrillation: Competing risk analysis from the Hokuriku-Plus AF Registry. Circ Rep 2022; 4: 298–307.
• 21.   Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1968; 405: 5–37.
• 22.   Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–2870.
• 23.   Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation. Chest 2010; 137: 263–272.
• 24.   Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010; 138: 1093–1100.
• 25.   Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236–239.
• 26.   Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. Intern Med 2001; 40: 1183–1188.
• 27.   Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 2013; 48: 452–458, doi:10.1038/bmt.2012.244.
• 28.   Hamaguchi S, Tsuchihashi-Makaya M, Kinugawa S, Yokota T, Takeshita A, Yokoshiki H, et al. Anemia is an independent predictor of long-term adverse outcomes in patients hospitalized with heart failure in Japan: A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 2009; 73: 1901–1908.
• 29.   Vaglio J, Safley DM, Rahman M, Kosiborod M, Jones P, Thompson R, et al. Relation of anemia at discharge to survival after acute coronary syndromes. Am J Cardiol 2005; 96: 496–499.
• 30.   Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review. Cancer 2001; 91: 2214–2221.
• 31.   Westenbrink BD, Alings M, Connolly SJ, Eikelboom J, Ezekowitz MD, Oldgren J, et al. Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: Insights from the RE-LY trial. J Thromb Haemost 2015; 13: 699–707.
• 32.   Westenbrink BD, Alings M, Granger CB, Alexander JH, Lopes RD, Hylek EM, et al. Anemia is associated with bleeding and mortality, but not stroke, in patients with atrial fibrillation: Insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J 2017; 185: 140–149.
• 33.   Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: The AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012; 60: 861–867.
• 34.   Murata N, Okumura Y, Nagashima K, Fukamachi D, Yokoyama K, Matsumoto N, et al. Gastrointestinal bleeding from oral anticoagulant therapy among Japanese patients with atrial fibrillation identified from the SAKURA Atrial Fibrillation Registry. Circ J 2020; 84: 1475–1482.
• 35.   Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM. Pathophysiology of anaemia: Focus on the heart and blood vessels. Nephrol Dial Transplant 2000; 15(Suppl 3): 14–18.
• 36.   Tanimura M, Dohi K, Fujimoto N, Moriwaki K, Omori T, Sato Y, et al. Effect of anemia on cardiovascular hemodynamics, therapeutic strategy and clinical outcomes in patients with heart failure and hemodynamic congestion. Circ J 2017; 81: 1670–1677.
• 37.   Kim IJ, Yang PS, Kim TH, Uhm JS, Pak HN, Lee MH, et al. Relationship between anemia and the risk of sudden cardiac arrest: A nationwide cohort study in South Korea. Circ J 2018; 82: 2962–2969.
• 38.   Tang WH, Tong W, Jain A, Francis GS, Harris CM, Young JB. Evaluation and long-term prognosis of new-onset, transient, and persistent anemia in ambulatory patients with chronic heart failure. J Am Coll Cardiol 2008; 51: 569–576.
• 39.   Hasin T, Sorkin A, Markiewicz W, Hammerman H, Aronson D. Prevalence and prognostic significance of transient, persistent, and new-onset anemia after acute myocardial infarction. Am J Cardiol 2009; 104: 486–491.
• 40.   Kalra PR, Cleland JGF, Petrie MC, Thomson EA, Kalra PA, Squire IB, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): An investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet 2022; 400: 2199–2209.
• 41.   Graham FJ, Pellicori P, Kalra PR, Ford I, Bruzzese D, Cleland JGF. Intravenous iron in patients with heart failure and iron deficiency: An updated meta-analysis. Eur J Heart Fail 2023; 25: 528–537.
• 42.   Tsutsui H, Ide T, Ito H, Kihara Y, Kinugawa K, Kinugawa S, et al. JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure. J Card Fail 2021; 27: 1404–1444.
• 43.   Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, et al. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: A post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol 2020; 8: 903–914.