10-Year Trends of Antithrombotic Therapy Status and Clinical Outcomes in Patients With Atrial Fibrillation and Renal Dysfunction　― The Fushimi AF Registry ―

Abstract

Background: Anticoagulation therapy for atrial fibrillation (AF) has undergone major changes following the introduction of direct oral anticoagulants (DOAC) in 2011. However, the transition of anticoagulation therapy for AF patients with severe renal dysfunction remains to be elucidated.

Methods and Results: Follow-up data, including creatinine clearance (CrCl), were available for 3,706 patients in the Fushimi AF Registry. We divided patients into 3 groups based on CrCl as follows: (1) CrCl ≥50 mL/min; (2) 50 mL/min>CrCl≥30 mL/min; and (3) CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50>CrCl≥30 mL/min, prescription of oral anticoagulants increased year-by-year from 2011 to 2021 with a growing proportion of DOAC; however, the prescription of oral anticoagulants remained almost unchanged in those with CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min, the incidence of adverse events, including stroke/systemic embolism and major bleeding, was lower among patients enrolled after 2014 than before 2013. However, these trends were not seen in patients with CrCl <30 mL/min.

Conclusions: Despite the increased use of DOAC in patients with AF since 2011, anticoagulation therapy for AF patients with severe renal dysfunction has largely remained unchanged, and a reduction in adverse events in those patients has not been observed.

Atrial fibrillation (AF) is a common arrhythmia that is associated with an increased risk of stroke and death.¹ Oral anticoagulants (OAC) are highly effective in reducing the risk of stroke, although their use is associated with bleeding complications. Until 2011, warfarin was the only available OAC; however, since 2011, direct oral anticoagulants (DOAC) that selectively inhibit coagulation factors have become available for stroke prevention in patients with AF. The prevalence of both AF and renal dysfunction increases with age;^2–4 therefore, AF and renal dysfunction often coexist in clinical practice. In randomized clinical trials of DOAC, approximately 20% of AF patients had chronic kidney disease.^5–8 Previous studies reported that approximately 30–60% of AF patients had renal dysfunction in the real-world clinical setting.^9–11 Renal dysfunction is strongly associated with an increased risk of cardiovascular events, including stroke, systemic embolism (SE), and cardiac death.^12–14 Moreover, renal dysfunction significantly affects the pharmacokinetics and safety of drugs that are mainly excreted through the kidney. All 4 DOAC depend on renal function to various degrees.¹⁵ The calculation of creatinine clearance (CrCl) is necessary to determine contraindications and doses of DOAC. Several studies have demonstrated the superiority of DOAC to warfarin in AF patients regardless of renal function.^16–18 However, physicians may hesitate to prescribe DOAC to AF patients with renal dysfunction due to concerns about an increased risk of bleeding. In the present study, using data from the Fushimi AF Registry, we investigated the transition of anticoagulation therapy and changes in the clinical outcomes of AF patients according to renal function over the past decade.

Methods

Data Source

The Fushimi AF Registry, a community-based prospective survey, was designed to enroll all AF patients who visited participating medical institutions in Fushimi-ku, Kyoto, Japan (University Hospital Medical Information Network [UMIN] Clinical Trials Registry ID: UMIN000005834). The detailed study design of the Fushimi AF Registry has been described previously.^19,20 The inclusion criterion for the registry was documentation of AF on a 12-lead electrocardiogram or Holter monitoring at any time. There were no exclusion criteria. In all, 81 institutions participated in the registry, comprising 2 cardiovascular centers (National Hospital Organization Kyoto Medical Center and Ijinkai Takeda Hospital), 10 small- and medium-sized hospitals, and 69 primary care clinics. Patient enrollment started in March 2011 and ended in May 2017. Annual collection of follow-up data was conducted primarily through medical record review, with additional follow-up data collected through contact with patients, relatives, and/or referring physicians by mail or telephone. Patient follow-up was finished in February 2022, and the longest follow-up period was 10 years.

The study protocol conformed to the ethics guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committees of the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital.

Study Population and Definitions

Figure 1 shows the patient flowchart. The entire cohort of this study consisted of 4,496 AF patients enrolled in the Fushimi AF Registry for whom follow-up data were available. In this analysis, we excluded 25 patients lacking data about prescriptions, 109 patients on dialysis, and 656 patients lacking data about renal function. Thus, 3,706 patients were included in this study for analysis. The median follow-up period was 2,016 days (interquartile range 824–3,211 days). We divided patients into 3 groups according to CrCl as follows: (1) CrCl ≥50 mL/min; (2) 50 mL/min>CrCl≥30 mL/min; and (3) CrCl <30 mL/min. Of the 3,706 AF patients, 2,351 (63.4%) were categorized in the CrCl ≥ 50 mL/min group, 979 (26.4%) were categorized in the 50 mL/min>CrCl≥30 mL/min group, and 376 (10.1%) were categorized in the CrCl <30 mL/min group.

Figure 1.

Patient flowchart for the present analysis. CrCl, creatinine clearance.

CrCl was calculated using the Cockcroft-Gault formula.²¹ We compared patient backgrounds among the 3 groups and investigated the year-by-year transition in OAC prescription status from 2011 to 2021. Furthermore, we subdivided each group into 2 according to the year of enrollment (2011–2013 and 2014–2017) to compare clinical outcomes before and after the release of the updated Japanese guidelines for AF published in 2014.²² Following the release of DOACs from 2011, the Japanese Circulation Society (JCS) guideline published in 2014 recommended,²² for the first time, using DOAC as first-line therapy in AF patients at risk of stroke. We believe that the 2014 JCS guideline played an important role in the more prevalent use of DOAC in real-world clinical practice.

In this study, we defined OAC as warfarin and DOAC as including dabigatran, rivaroxaban, apixaban, and edoxaban. Antiplatelet drugs included aspirin, ticlopidine, clopidogrel, prasugrel, and cilostazol. We assessed the risk of stroke using the CHADS₂ score²³ and the CHA₂DS₂-VASc score,²⁴ and assessed bleeding risk using the HAS-BLED score.²⁵ The “V” in the CHA₂DS₂-VASc score was defined as prior myocardial infarction or peripheral artery disease. The “L” in the HAS-BLED score was not incorporated in this analysis, because the international normalized ratio was only checked at enrollment.

Outcomes

The primary outcomes of this study were the composite of stroke or SE as the thromboembolic event, and major bleeding as the bleeding event. Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery, and confirmed on computed tomography or magnetic resonance imaging. SE was defined as an acute vascular occlusion of an extremity or organ. Major bleeding was defined as a reduction in hemoglobin level by at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ, following the definition of the International Society on Thrombosis and Hemostasis.²⁶ As secondary endpoints, we evaluated all-cause death, cardiac death, myocardial infarction, hospitalization due to heart failure, and a composite of cardiac death, myocardial infarction, stroke, or SE.

Statistical Analysis

Continuous variables are expressed as the mean±SD and were compared using the Kruskal-Wallis test or Wilcoxon rank-sum test. Categorical variables are presented as numbers and percentages and were compared using the Chi-squared test when appropriate; otherwise, Fisher’s exact test was used. The Kaplan-Meier method was used to estimate the cumulative incidence of clinical events, and the log-rank test was used to compare differences among the groups. A Cox proportional hazards model was used to compare outcomes among groups, with the results expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Furthermore, we performed multivariate Cox proportional hazard analysis adjusted by all the components of the CHA₂DS₂-VASc score for all clinical events other than major bleeding, and all the components of the HAS-BLED score for major bleeding. Significance was set at 2-sided P<0.05. Data analysis was performed using JMP version 16 (SAS Institute, Cary, NC, USA).

Results

Baseline Characteristics

Table 1 presents the baseline characteristics of patients according to the 3 CrCl strata. Age, body mass index and type of AF were different among 3 groups. Prevalences of comorbidities such as a history of stroke, congestive heart failure, coronary artery disease, and hypertension were different among 3 groups. The CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores were significantly different among 3 groups (all P<0.01). Prescription of OAC was different among 3 groups. Prescription of antiplatelet drugs was also different among 3 groups.

Table 1.

Baseline Characteristics and Medication Use According to Creatinine Clearance

	CrCl ≥50 mL/min	50 mL/min>CrCl≥30 mL/min	CrCl <30 mL/min	P value
No. patients	2,351	979	376
Male sex	1,609 (68.4)	456 (46.6)	139 (37.0)	<0.01
Age (years)	69.9±9.7	80.3±7.1	83.9±8.0	<0.01
Height (cm)	162.9±9.1	155.5±9.4	152.4±9.8	<0.01
Body weight (kg)	64.1±12.7	52.6±10.6	48.3±11.2	<0.01
Low body weight (≤50 kg)	282 (12.0)	446 (45.6)	232 (61.7)	<0.01
Body mass index (kg/m2)	24.1±4.0	21.7±3.5	20.7±3.7	<0.01
SBP (mmHg)	126±17	124±19	121±21	<0.01
DBP (mmHg)	73±12	69±13	65±15	<0.01
Pulse rate (beats/min)	78±16	79±17	78±19	0.44
Type of AF
Paroxysmal AF	1,157 (49.2)	451 (46.1)	174 (46.3)	0.02
Persistent AF	269 (11.4)	104 (10.6)	28 (7.4)
Permanent AF	925 (39.3)	424 (43.3)	174 (46.3)
Stroke	360 (15.3)	206 (21.0)	95 (25.3)	<0.01
Coronary artery disease	306 (13.0)	165 (16.9)	90 (23.9)	<0.01
MI	119 (5.1)	57 (5.8)	53 (14.1)	<0.01
History of PCI	175 (7.4)	93 (9.5)	49 (13.0)	<0.01
History of CABG	49 (2.1)	22 (2.2)	14 (3.7)	0.18
Peripheral artery disease	82 (3.5)	61 (6.2)	14 (3.7)	<0.01
SE	27 (1.1)	13 (1.3)	5 (1.3)	0.89
Congestive HF	493 (21.0)	387 (39.5)	226 (60.1)	<0.01
Hypertension	1,463 (62.2)	665 (67.9)	261 (69.4)	<0.01
Diabetes	614 (26.1)	223 (22.8)	92 (24.5)	0.12
Dyslipidemia	1,116 (47.5)	431 (44.0)	155 (41.2)	0.03
COPD	120 (5.1)	72 (7.4)	23 (6.1)	0.04
Major bleeding	101 (4.3)	44 (4.5)	24 (6.4)	0.23
CHADS2 score	1.8±1.3	2.6±1.2	2.9±1.2	<0.01
CHA2DS2-VASc score	2.9±1.6	4.2±1.4	4.7±1.4	<0.01
HAS-BLED score	1.6±1.0	1.9±0.9	2.5±1.1	<0.01
Oral anticoagulant	1,327 (56.4)	598 (61.1)	174 (46.3)	<0.01
Warfarin	919 (39.1)	462 (47.2)	149 (39.6)	<0.01
Direct oral anticoagulant	408 (17.4)	136 (13.9)	25 (6.6)	<0.01
Antiplatelet drug	566 (24.1)	292 (29.8)	135 (35.9)	<0.01
ACEi/ARB	1,005 (42.7)	500 (51.1)	207 (55.1)	<0.01
β-blocker	692 (29.4)	328 (33.5)	139 (37.0)	<0.01
Calcium channel blocker	1,005 (42.7)	375 (38.3)	159 (42.3)	0.06
Diuretic	519 (22.1)	394 (40.2)	225 (59.8)	<0.01
Antidiabetic agent	333 (14.2)	129 (13.2)	47 (12.5)	0.57
Insulin	72 (3.1)	38 (3.9)	20 (5.3)	0.08
Oral hypoglycemic agent	288 (12.3)	105 (10.7)	33 (8.8)	0.09
Statin	622 (26.5)	250 (25.5)	97 (25.8)	0.85
Digitalis	269 (11.4)	124 (12.7)	33 (8.8)	0.12
Antiarrhythmic drug	466 (19.8)	157 (16.0)	39 (10.4)	<0.01

Categorical data are presented as n (%); continuous data are presented as the mean±SD. ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; DBP, diastolic blood pressure; HF, heart failure; MI, myocardial infarction; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; SE, systemic embolism.

A comparison of baseline characteristics of patients enrolled before 2013 and after 2014 is presented in the Supplementary Table. CHADS₂ and CHA₂DS₂-VASc were similar between patients enrolled before 2013 and after 2014 in the CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min groups. In the CrCl <30 mL/min group, they were higher for patients enrolled after 2014 than for those enrolled before 2013.

Year-by-Year Transitions in OAC Prescriptions

Follow-up data, including prescription data, were collected every year and Figure 2 shows the year-by-year transitions in OAC prescriptions from 2011 to 2021 according to CrCl stratum. Data for each year are not for newly registered patients, but for accumulated patients. In 2011, 54.1%, 59.4%, and 42.2% of patients in the CrCl ≥50 mL/min, 50 mL/min>CrCl≥30 mL/min, and CrCl <30 mL/min groups, respectively, were prescribed an OAC. The proportion of patients with OAC increased year-by-year in the CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min groups, but remained unchanged in the CrCl <30 mL/min group. In 2021, 72.5%, 72.3%, and 42.5% of patients in the CrCl ≥50 mL/min, 50 mL/min>CrCl≥30 mL/min, and CrCl <30 mL/min groups, respectively, had an OAC.

Figure 2.

Year-by-year transitions in anticoagulant therapy status from 2011 to 2021 according to creatinine clearance (CrCl) stratum. DOAC, direct oral anticoagulant; OAC, oral anticoagulant.

After the launch of DOACs, the anticoagulation strategy for AF patients underwent a major change. In 2011, when dabigatran, the first DOAC, was launched, the proportion of patients with a DOAC prescription was very low, but since then DOAC prescriptions increased year-by-year, especially in the CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min groups.

Clinical Outcomes

Kaplan-Meier curves for the incidence of stroke/SE in patients enrolled before 2013 and after 2014 according to CrCl stratum are shown in Figure 3. In the CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min groups, the incidence rate (percentage per patient-year) of stroke/SE was lower among patients enrolled after 2014 than before 2013 (CrCl ≥50 mL/min: 1.9% vs. 1.3%; log-rank P=0.02, 50 mL/min>CrCl≥30 mL/min: 3.2% vs. 1.6%; log-rank P=0.02). In the CrCl <30 mL/min group, the incidence of stroke/SE did not differ significantly between patients enrolled before 2013 and after 2014 (4.8% vs. 2.6%; log-rank P=0.14).

Figure 3.

Kaplan-Meier curves for stroke or systemic embolism (SE) according to creatinine clearance (CrCl) stratum. The incidence rates are shown as the percentage per patient-year.

Kaplan-Meier curves for the incidences of major bleeding are shown in Figure 4. In the CrCl ≥50 mL/min group, the incidence rate (percentage per patient-year) of major bleeding was lower among patients enrolled after 2014 than before 2013 (1.7% vs. 1.1%; log-rank P=0.02). In the 50 mL/min>CrCl≥30 mL/min and CrCl <30 mL/min groups, the incidence of major bleeding did not differ significantly between patients enrolled before 2013 and after 2014 (50 mL/min>CrCl≥30 mL/min: 2.3% vs. 2.2%; log-rank P=0.93, CrCl <30 mL/min: 4.3% vs. 4.7%; log-rank P=0.75).

Figure 4.

Kaplan-Meier curves for major bleeding according to creatinine clearance (CrCl) stratum. The incidence rates are shown as the percentage per patient-year.

Table 2 presents results of univariate and multivariate analyses of primary and secondary outcomes. Multivariate Cox proportional hazard analysis revealed that the incidence of stroke/SE was significantly lower among patients enrolled after 2014 than before 2013 in both the CrCl ≥50 mL/min (HR 0.68; 95% CI 0.47–0.995) and 50 mL/min>CrCl≥30 mL/min (HR 0.52; 95% CI 0.30–0.89) groups. In patients with CrCl ≥50 mL/min, the incidence of major bleeding were significantly lower in patients enrolled after 2014 than before 2013 (HR 0.64; 95% CI 0.43–0.96).

Table 2.

Incidence of Major Clinical Events According to Creatinine Clearance

	Enrolled before 2013		Enrolled after 2014		Unadjusted HR vs. enrolled before 2013 (95% CI)	Adjusted HR vs. enrolled before 2013 (95% CI)
	n	% per patient-year	n	% per patient-year
CrCl ≥50 mL/min
No. patients	1,815		536
Stroke/SE	218	1.9	32	1.3	0.64 (0.44–0.93)	0.68 (0.47–0.995)
Major bleeding	195	1.7	28	1.1	0.61 (0.41–0.92)	0.64 (0.43–0.96)
All-cause death	397	3.3	66	2.5	0.79 (0.60–1.03)	0.84 (0.65–1.11)
Cardiac death	54	0.5	8	0.3	0.70 (0.33–1.50)	0.82 (0.38–1.76)
MI	21	0.2	3	0.1	0.60 (0.18–2.05)	0.61 (0.18–2.07)
Hospitalization due to HF	245	2.2	57	2.3	1.04 (0.78–1.40)	1.11 (0.82–1.49)
Composite of cardiac death, MI, stroke, or SE	276	2.5	42	1.7	0.66 (0.48–0.92)	0.72 (0.52–1.01)
50 mL/min>CrCl≥30 mL/min
No. patients	757		222
Stroke/SE	109	3.2	15	1.6	0.52 (0.30–0.90)	0.52 (0.30–0.89)
Major bleeding	80	2.3	20	2.2	0.98 (0.59–1.61)	0.98 (0.59–1.63)
All-cause death	324	9.0	70	7.2	0.81 (0.62–1.05)	0.82 (0.63–1.07)
Cardiac death	57	1.6	17	1.7	1.06 (0.61–1.83)	0.98 (0.57–1.71)
MI	6	0.2	2	0.2	1.08 (0.22–5.39)	0.93 (0.18–4.77)
Hospitalization due to HF	168	5.3	47	5.4	1.03 (0.74–1.44)	0.92 (0.66–1.28)
Composite of cardiac death, MI, stroke, or SE	162	4.8	33	3.5	0.74 (0.51–1.09)	0.72 (0.49–1.06)
CrCl <30 mL/min
No. patients	300		76
Stroke/SE	45	4.8	6	2.6	0.53 (0.23–1.25)	0.51 (0.22–1.21)
Major bleeding	39	4.3	10	4.7	1.12 (0.55–2.27)	1.01 (0.49–2.08)
All-cause death	179	17.9	43	18.4	0.99 (0.71–1.39)	0.95 (0.68–1.33)
Cardiac death	39	3.9	8	3.4	0.88 (0.41–1.90)	0.85 (0.39–1.85)
MI	10	1.0	1	0.4	0.37 (0.05–2.92)	0.20 (0.02–1.99)
Hospitalization due to HF	93	11.5	25	13.8	1.14 (0.73–1.78)	1.08 (0.69–1.69)
Composite of cardiac death, MI, stroke, or SE	85	9.2	14	6.1	0.66 (0.38–1.17)	0.64 (0.36–1.14)

In the multivariate analysis, we added each component of the CHA₂DS₂-VASc score for clinical events other than major bleeding, and each component of the HAS-BLED score for major bleeding. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Discussion

There are 2 major findings of the present analysis. First, after the launch of DOAC, in AF patients with CrCl ≥50 mL/min or 50 mL/min>CrCl≥30 mL/min, the proportion of OAC prescriptions increased progressively year-by-year, with the predominant use of DOAC. However, in AF patients with CrCl <30 mL/min, there was no change in the proportion of OAC prescriptions. Second, in AF patients with CrCl ≥50 mL/min or 50 mL/min>CrCl≥30 mL/min, the incidence of adverse events was lower among patients enrolled after 2014 than before 2013. However, in AF patients with CrCl <30 mL/min, there was no difference in the incidence of adverse events between patients enrolled before 2013 and after 2014.

Transition in OAC Therapy in Patients With Renal Dysfunction

We previously reported that the use of OAC, especially DOAC, increased steadily over the decade from 2011 to 2021.²⁷ In the present study, there was no significant change in the use of OAC in AF patients with severe renal dysfunction over the same time period. The proportion of AF patients with a prescription for OAC varies according to patient background and time of enrollment. In the J-RHYTHM Registry, which enrolled patients during the warfarin era, over 80% of Japanese AF patients received a warfarin prescription regardless of renal function.¹⁴ Conversely, only half of Japanese AF patients received an OAC prescription in the Fushimi AF Registry.¹² In the ANAFIE Registry, in which patients were enrolled in the DOAC era, over 90% of AF patients with CrCl ≥15 mL/min received an OAC prescription and over 60% of those patients received a DOAC prescription.²⁸ In the international GARFIELD Registry, approximately 70% of AF patients received an OAC prescription, regardless of renal function.¹³ These studies reported on the proportion of AF patients with an OAC prescription, but few studies have investigated changes in OAC prescriptions over time. The present analysis, which revealed the transition of OAC therapy from the warfarin era to the DOAC era in patients with renal dysfunction, is thought to provide important information in contemporary practice in Japan. AF patients with renal dysfunction are known to have an increased risk of stroke and major bleeding.^12,13,29,30 Warfarin is associated with a higher risk of bleeding regardless of renal function,³⁰ and AF patients with severe renal dysfunction are more likely to have poor control of time in the therapeutic range of warfarin.³¹ For these reasons, physicians are likely to hesitate to prescribe warfarin to AF patients with renal dysfunction. After the release of DOACs, they have been widely prescribed for AF patients. In subanalyses of randomized clinical trials, DOAC were consistently found to be effective and safe compared with warfarin in AF patients with renal dysfunction.^16,17,32 However, AF patients with CrCl <30 or <25 mL/min were excluded from 4 randomized clinical trials of DOAC.^5–8 Real-world clinical data are limited in AF patients with CrCl <30 mL/min, which may explain why DOAC prescriptions have not become prevalent in AF patients with severe renal dysfunction. Another reason why DOAC prescriptions did not increase among AF patients with CrCl <30 mL/min may be the discrepancy in the approved CrCl range of 15–30 mL/min between dabigatran and Factor Xa inhibitors. Dabigatran is approved for use in AF patients with CrCl ≥30 mL/min, whereas Factor Xa inhibitors are approved for use in those with CrCl ≥15 mL/min. This difference may confuse physicians when it comes to prescribing DOAC to AF patients with CrCl <30 mL/min.

Changes in Clinical Outcomes of Patients With Renal Dysfunction

We also reported previously that incidence of stroke/SE and major bleeding decreased over the decade from 2011 to 2021.²⁷ The Shinken Database also reported that the incidence of thromboembolism decreased with the dawn of the DOAC era.³³ An increase in DOAC prescriptions was thought to contribute to the improved outcomes of AF patients. In the present analysis, the incidence of both stroke/SE and major bleeding decreased in AF patients with CrCl ≥50 mL/min enrolled after 2014 compared with those enrolled before 2013. Furthermore, the incidence of stroke/SE decreased in AF patients with 50 mL/min>CrCl≥30 mL/min enrolled after 2014 compared with those enrolled before 2013. A meta-analysis of randomized clinical trials of DOAC revealed that the use of DOAC was associated with a risk reduction of stroke/SE and major bleeding compared with warfarin in AF patients with renal dysfunction.³⁴ In the present study, an increase in the proportion of patients prescribed DOAC may have contributed to the reduction in stroke/SE and major bleeding in the groups with CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min. In the present analysis, there were no improvements in any clinical outcomes over time among AF patients with CrCl <30 mL/min. A subanalysis of ANAFIE Registry demonstrated that in the 30 mL/min>CrCl≥15 mL/min group, the incidence of stroke/SE and major bleeding was similar between patients prescribed DOAC and those prescribed warfarin, but the incidence of cardiac events, hospitalization due to heart failure, and cardiovascular events was lower among patients prescribed DOAC than those prescribed warfarin.³⁵ In the subanalysis, not administrating OAC was associated with a higher incidence of stroke/SE and all cause death.³⁵ For these reasons, the prescription of DOAC for AF patients with 30 mL/min>CrCl≥15 mL/min, unless contraindicated, is considered an acceptable option and is a Class IIa recommendation in the latest 2024 Japanese guidelines focus update for arrhythmia treatment.³⁶ In the present analysis, in the CrCl <30 mL/min group, the proportion of patients with a prescription for OAC did not change over time, and there was no increase in the use of DOAC. This may be one reason why there was no significant improvement in any of the clinical events in the CrCl <30 mL/min group over time.

Study Limitations

This study has several limitations. First, the Fushimi AF Registry was a prospective observational study; therefore, it only shows associations. Second, CrCl data were not available for approximately 15% of patients of the registry. Although we divided patients into 3 groups according to their CrCl at enrollment, there may have been changes in CrCl during the follow-up period. A previous study reported that patients with DOAC have a slower decline in renal function than those receiving warfarin,³⁷ which may have influenced the incidence of events. Third, we categorized all patients based on OAC prescription at enrollment in this analysis. Prescription data were collected every year and many patients underwent several transitions in OAC status during the follow-up period. It was difficult to take transitions in OAC status into consideration in this analysis. Fourth, the number of the patients with CrCl <30 mL/min enrolled after 2014 was too small to allow statistical comparisons. Finally, this registry included a Japanese-only population recruited from a small region of Japan, limiting the generalizability of the results.

Conclusions

Despite a more prevalent use of DOAC in the past decade, anticoagulation therapy has remained unchanged in AF patients with severe renal dysfunction, and there has been no reduction in adverse events in this patient group.

Acknowledgments

The authors sincerely appreciate the help of all the institutions participating in the registry and the clinical research coordinators (T. Shinagawa, M. Mitamura, M. Fukahori, M. Kimura, M. Fukuyama, C. Kamata, and N. Nishiyama).

Sources of Funding

This research was supported, in part, by the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from the Japan Agency for Medical Research and Development, AMED (19ek0210082 h0003, 18ek0210056 h0003). The Fushimi AF Registry was supported by research funding from Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Disclosures

M. Akao has received research funding from Bayer Yakuhin, scholarship funds from Bayer Yakuhin and Daiichi Sankyo, and lecture fees from Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, and Daiichi Sankyo. All other authors have no relationships relevant to the content of this paper to disclose.

IRB Information

The study protocol was approved by the ethics committees of the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital (Reference no. 10-058 and 14-033, respectively).

Data Availability

Deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0614

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