Renal Dysfunction Affects Anticoagulation Control With Warfarin and Outcomes in Japanese Elderly Patients With Non-Valvular Atrial Fibrillation

Abstract

Background: It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF).

Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged ≥70 years. Target INR values were 1.6–2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13–1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37–3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41–6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56–18.18, P=0.008 and 1.60, 1.07–2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10–3.76, P=0.024 and 1.58, 1.22–2.04, P=0.001, respectively).

Conclusions: Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death.

Chronic kidney disease or renal dysfunction is a risk factor for incident atrial fibrillation (AF).^1,2 Once AF is established, renal dysfunction is a risk factor for stroke, hemorrhage, and all-cause death.^3–7 AF patients with renal dysfunction require lower doses for warfarin maintenance and have impaired anticoagulation control.^8–11 Reports on the relationships among renal dysfunction, anticoagulation control with warfarin, and clinical outcomes are still limited in Asian patients with non-valvular AF (NVAF).^12–15 We recently reported that lower creatinine clearance (CrCl) values in NVAF patients were associated with thromboembolism and all-cause death in a subanalysis of the J-RHYTHM Registry.¹⁶ In that analysis, however, the relation between the quality of warfarin control and CrCl values or outcomes was not determined.¹⁶ The target international normalized ratio (INR) of prothrombin time for elderly NVAF patients is different between Japanese¹⁷ and Western guidelines.¹⁸ Japanese physicians tend to select lower INR values than recommended, even for younger NVAF patients. For instance, in the J-RHYTHM Registry, baseline INR values were below the recommended values of 2.0–3.0 in 60% of patients aged <70 years.¹⁹ The present analysis was, therefore, performed to determine the relationships among renal function, quality of warfarin control, and outcomes over a 2-year follow-up period in elderly Japanese NVAF patients aged ≥70 years using a dataset from the J-RHYTHM Registry.^19,20

Methods

The J-RHYTHM Registry (UMIN Clinical Trials Registry UMIN 000001569) was a prospective observational investigation, and enrolled patients with AF of any type from January to July 2009 after receiving written informed consent.²⁰

Study Protocol

The study design and baseline patient characteristics have been reported elsewhere.^19,20 Briefly, the study protocol conformed to the Declaration of Helsinki and was approved by the ethics committee of each participating institution. A consecutive series of outpatients with AF of any type was enrolled without any exclusion criterion regarding renal function. Patients were excluded from the present analysis if they had mitral stenosis, had undergone mechanical valve replacement, or were lost to follow-up during the follow-up period, as were those to whom warfarin was not given or in whom baseline renal function data were not available. Antithrombotic drugs and dosages were selected at the discretion of treating physicians. Anticoagulation intensity was determined using INR values at least once every 2 months.²⁰ The time in therapeutic range (TTR) was determined as an index of quality of warfarin control using the method developed by Rosendaal et al.²¹ For determination of TTR, the target INR level was set at 1.6–2.6 for elderly patients aged ≥70 years according to Japanese guidelines.¹⁷ Patients were divided into 2 groups based on TTR values: TTR <65% vs. TTR ≥65%.²²

Using the data on age, sex, body weight, and serum creatinine value at the time of enrollment, CrCl was calculated by the Cockcroft-Gault formula.²³ Patients were divided into the following 4 groups based on CrCl values: <30 mL/min, 30–49.9 mL/min, 50–79.9 mL/min, and ≥80 mL/min.²⁴

Endpoints

Patients were followed for 2 years or until the occurrence of an event, whichever came first. Primary endpoints were thromboembolism, including symptomatic ischemic stroke, transient ischemic attack (TIA) and systemic embolic events; major hemorrhage, including intracranial hemorrhage, gastrointestinal hemorrhage and other hemorrhage requiring hospitalization; or all-cause death. The composite of thromboembolism, major hemorrhage, and all-cause death was also evaluated. The diagnostic criteria for each event have been described elsewhere.²⁰

Statistical Analysis

Data are presented as mean±standard deviation. The significance of differences in mean values was analyzed using Student’s t-test or analysis of variance, as appropriate. Frequencies of parameters or events were compared using the chi-square test or Fisher’s exact test, as appropriate. Kaplan-Meier curves were used to compare time to events with log-rank tests. Logistic regression analysis was used to determine the variables that were associated with lower TTR values (<65%). Explanatory variables in the univariate analysis were age, sex, comorbidities, type of AF, heart rate, blood pressure, medications, body mass index, and CrCl. The variables in the multivariate analysis were selected from the significant variables in the univariate analysis. A Cox proportional hazards model was used to investigate the influence of CrCl and TTR values on events. Hazard ratios (HRs) and 95% confidence interval (CI) of the groups with CrCl <80 mL/min were calculated with the CrCl ≥80 mL/min group as a reference. Explanatory variables for the multivariate analysis were adopted from well-known risk factors, such as components of the CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and history of stroke or TIA, vascular disease [coronary artery disease in the present study], and female sex),²⁵ and medications. Two-tailed P value <0.05 was considered significant. All statistical analyses were performed with SPSS software version 23.0 (IBM Corporation, Armonk, NY, USA).

Results

Of 7,937 AF patients enrolled into the registry, 421 patients had mitral stenosis or had undergone mechanical valve replacement, and another 110 patients were lost to follow-up. Therefore, follow-up data were available for 7,406 patients with NVAF. Of these, baseline CrCl data were missing for 1,354 patients. Of the remaining 6,052 patients who had baseline CrCl data, TTR values were available for 4,996 patients, and of these, 2,782 patients aged ≥70 years constituted the study group of the present analysis.

Patients’ Clinical Characteristics

The characteristics of the patients are shown in Table 1. TTR was ≥65% in 1,937 (70%) patients. Compared with the higher TTR group (≥65%), the lower TTR group (<65%) was older, and had lower body weight, lower CrCl values, and higher prevalence of some comorbidities. Consequently, thromboembolic (CHADS₂ and CHA₂DS₂-VASc)^25,26 and hemorrhagic risk (HAS-BLED)²⁷ scores were higher in the lower TTR group than in the higher TTR group. Daily doses of warfarin and baseline INR values were lower in the lower TTR group than in the higher TTR group.

Table 1. Patients’ Characteristics and Medications

	Overall (n=2,782)	INR control		P value**
		TTR* <65% (n=845)	TTR* ≥65% (n=1,937)
Age, years	75±5	78±5	77±5	<0.001
Sex, female	980 (35)	298 (35)	682 (35)	0.977
Body weight, kg	59±12	58±15	59±11	0.020
CrCl, mL/min	54±20	52±21	56±19	<0.001
Type of AF
Paroxysmal	884 (32)	265 (31)	619 (32)	0.469
Persistent	362 (13)	120 (14)	242 (12)
Permanent	1,536 (55)	460 (54)	1,076 (56)
Comorbidities
CAD	377 (14)	131 (16)	246 (13)	0.047
Cardiomyopathy	201 (7)	57 (7)	144 (7)	0.519
COPD	71 (3)	24 (3)	47 (2)	0.524
Hyperthyroidism	35 (1)	7 (1)	28 (1)	0.179
Risk factors for stroke
Heart failure	922 (33)	323 (38)	599 (31)	<0.001
Hypertension	1,855 (67)	548 (65)	1,307 (67)	0.177
Age (≥75 years)	1,729 (62)	565 (67)	1,164 (60)	<0.001
Diabetes mellitus	573 (21)	188 (22)	385 (20)	0.155
Stroke/TIA	468 (17)	140 (17)	328 (17)	0.813
CHADS2 score	2.1±1.2	2.3±1.2	2.1±1.2	0.009
CHA2DS2-VASc score	3.6±1.4	3.8±1.3	3.6±1.4	0.005
HAS-BLED score	1.9±0.9	2.0±0.9	1.8±0.8	<0.001
Warfarin
Dosage, mg/day	2.6±1.0	2.4±1.1	2.7±1.0	<0.001
Baseline INR	1.89±0.48	1.80±0.58	1.94±0.42	<0.001
No. of times INR measured	14±5	13±6	14±5	<0.001
TTR,* %	73±23	44±18	85±11	<0.001
Antiplatelet drugs	707 (25)	255 (30)	452 (23)	<0.001
Aspirin	590 (21)	203 (24)	387 (20)	0.016
Other	190 (7)	84 (10)	106 (5)	<0.001

Data are number of patients (%) or mean±SD. *Target INR was 1.6–2.6. **Comparison between groups with TTR <65% and ≥65%. AF, atrial fibrillation; CAD, coronary artery disease; CrCl, creatinine clearance; CHADS₂, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and history of stroke or TIA; CHA₂DS₂-VASc, CHADS₂ components plus vascular disease (coronary artery disease), age 65–74 years, and female sex; COPD, chronic obstructive pulmonary disease; HAS-BLED, hypertension (systolic blood pressure ≥140 mmHg), abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR (episodes of INR ≥3.5), elderly (age >65 years), drugs (use of antiplatelet drugs)/alcohol concomitantly; INR, international normalized ratio of prothrombin time; TIA, transient ischemic attack; TTR, time in therapeutic range.

In Table 2, the characteristics of the 4 CrCl groups are shown. Prevalence rates of hypertension, diabetes mellitus, and stroke were comparable, but those of several variables differed significantly among the groups. In particular, age and prevalence of coronary artery disease, cardiomyopathy, and heart failure were higher in the group with CrCl <30 mL/min. Consequently, the CrCl <30 mL/min group had higher thromboembolic and hemorrhagic risk scores. Although baseline INR values did not differ among the 4 CrCl groups, daily doses of warfarin and TTR values differed significantly among the groups, with the CrCl <30 mL/min group having the lowest values.

Table 2. Patients’ Characteristics Stratified by CrCl

	CrCl (mL/min)				P value for trend
	<30 (n=270)	30–49.9 (n=908)	50–79.9 (n=1,358)	≥80 (n=246)
Age, years	81±5	79±5	75±4	74±3	<0.001
Sex, female	149 (55)	364 (40)	406 (30)	61 (25)	<0.001
Body weight, kg	49±10	54±9	62±9	71±21	<0.001
CrCl, mL/min	23±6	41±6	63±8	92±17	<0.001
Type of AF
Paroxysmal	84 (31)	284 (31)	446 (33)	70 (28)	0.587
Persistent	30 (11)	105 (12)	198 (15)	29 (12)
Permanent	156 (58)	519 (57)	714 (52)	147 (60)
Comorbidities
CAD	58 (21)	147 (16)	147 (11)	25 (10)	<0.001
Cardiomyopathy	29 (11)	66 (7)	95 (7)	11 (4)	0.015
COPD	3 (1)	32 (4)	30 (2)	6 (2)	0.839
Hyperthyroidism	6 (2)	10 (1)	15 (1)	4 (2)	0.533
Risk factors for stroke
Heart failure	170 (63)	367 (40)	332 (24)	53 (22)	<0.001
Hypertension	182 (67)	598 (66)	900 (66)	175 (71)	0.458
Age (≥75 years)	234 (87)	711 (78)	701 (52)	83 (34)	<0.001
Diabetes mellitus	63 (23)	181 (20)	268 (20)	61 (25)	0.925
Stroke/TIA	45 (17)	174 (19)	214 (16)	35 (14)	0.084
CHADS2 score	2.7±1.1	2.4±1.2	1.9±1.2	1.8±1.1	<0.001
CHA2DS2-VASc score	4.5±1.3	4.0±1.3	3.3±1.3	3.1±1.3	<0.001
HAS-BLED score	2.2±1.0	1.9±0.9	1.8±0.8	1.8±1.8	<0.001
Warfarin
Dosage, mg/day	2.1±0.9	2.4±0.9	2.8±1.1	3.0±1.1	<0.001
Baseline INR	1.88±0.53	1.91±0.51	1.89±0.46	1.90±0.46	0.564
No. of times INR measured	14±61	14±5	14±5	14±5	0.990
TTR,* %	65±25	72±24	74±22	76±22	<0.001
Antiplatelet drugs	85 (31)	265 (29)	301 (22)	56 (23)	<0.001
Aspirin	64 (24)	217 (24)	257 (19)	52 (21)	0.024
Other	31 (11)	72 (8)	78 (6)	9 (4)	<0.001

Data are number of patients (%) or mean±SD. *Target INR was 1.6–2.6. Abbreviations as in Table 1.

In the multivariate logistic regression analysis, age ≥75 years, heart failure, antiplatelet use, body mass index <25 kg/m², and CrCl <30 mL/min were independently associated with TTR values of <65% (Table 3).

Table 3. Determinants of TTR <65% (Logistic Regression Analysis)

Explanatory variables	Univariate		Multivariate
	OR (95% CI)	P value	OR (95% CI)	P value
Age (≥75 years)	1.38 (1.17–1.64)	<0.001	1.24 (1.04–1.48)	0.016
Heart failure	1.34 (1.13–1.59)	0.001	1.23 (1.03–1.47)	0.020
CAD	1.26 (1.003–1.59)	0.047	1.03 (0.80–1.33)	0.828
Antiplatelet use	1.42 (1.19–1.70)	<0.001	1.37 (1.13–1.67)	0.002
BMI ≥25 kg/m2	0.78 (0.65–0.94)	0.010	0.82 (0.68–0.99)	0.038
CrCl <30 mL/min	1.81 (1.40–2.34)	<0.001	1.49 (1.13–1.95)	0.004

Explanatory variables in the univariate analysis were: heart failure, hypertension, age ≥75 years, diabetes mellitus, history of stroke or transient ischemic attack, CAD, female sex, cardiomyopathy, congenital heart disease, chronic obstructive pulmonary disease, hyperthyroidism, abnormal liver function, CrCl (<30 mL/min), type of AF, systolic blood pressure, diastolic blood pressure, heart rate, BMI (≥25 kg/m²), and use of antiplatelets, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and statins. Variables with a P value ≥0.05 in the univariate logistic regression analysis are not shown here. Explanatory variables in the multivariate logistic regression analysis were selected from the significant variables in the univariate analysis. BMI, body mass index; CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Event Rates

During the 2-year follow-up period, 63 patients had thromboembolic events, 75 had major hemorrhagic events, and 100 died (Table 4). Incidences were significantly higher for thromboembolism and all-cause death, and numerically higher for major hemorrhage in the lower TTR group than in the higher TTR group. Consequently, the rate of the composite event was higher in the lower TTR group than in the higher TTR group. As for the relationship of CrCl values to events, there was a significant trend for all-cause death among the 4 CrCl groups (P<0.001 for trend). The CrCl <30 mL/min group had numerically the highest event rates for thromboembolism and major hemorrhage among the 4 groups. Consequently, the composite event rate showed a significant trend among the 4 groups (P<0.001 for trend) with the CrCl <30 mL/min group having the highest rate (Table 4). The Kaplan-Meier curves for the composite event were compared between the 2 TTR groups (Figure). The event-free rate of the composite event was higher in the higher TTR group than in the lower TTR group for each CrCl group, except for the CrCl <30 mL/min group.

Table 4. The 2-Year Event Rates in Groups Stratified by TTR (A) and CrCl (B)

A	Overall (n=2,782)	TTR (%)		P value*
		<65 (n=845)	≥65 (n=1,937)
Thromboembolism	63 (2.3)	31 (3.7)	32 (1.7)	0.001
Major hemorrhage	75 (2.7)	26 (3.1)	49 (2.5)	0.412
All-cause death	100 (3.6)	45 (5.3)	55 (2.8)	0.001
Composite event**	238 (8.6)	102 (12.1)	136 (7.0)	<0.001
B	CrCl (mL/min)				P value for trend
	<30 (n=270)	30–49.9 (n=908)	50–79.9 (n=1,358)	≥80 (n=246)
Thromboembolism	7 (2.6)	22 (2.4)	31 (2.3)	3 (1.2)	0.348
Major hemorrhage	11 (4.1)	29 (3.2)	26 (1.9)	9 (3.7)	0.153
All-cause death	29 (10.8)	44 (4.8)	24 (1.8)	3 (1.2)	<0.001
Composite event**	47 (17.4)	95 (10.5)	81 (6.0)	15 (6.1)	<0.001

Data are number of patients (%). *Comparison between groups with TTR of <65% and ≥65%. **Thromboembolism, major hemorrhage, and all-cause death. Abbreviations as in Table 1.

Figure.

Kaplan-Meier curves for the composite of thromboembolism, major hemorrhage, and all-cause death. See text for details. CrCl, creatinine clearance; TTR, time in therapeutic range.

In the multivariate analysis (Table 5), TTR <65% was associated with an increased risk of thromboembolism, all-cause death, and the composite event. By contrast, CrCl values were not associated with thromboembolism or major hemorrhage; only CrCl <30 mL/min was associated with an increased risk of all-cause death and the composite event. A significant interaction was observed between TTR and CrCl for all-cause death and the composite event (Table 5). The composite event rate was lower in the higher TTR group than in the lower TTR group for each CrCl group, except for the CrCl <30 mL/min group (Figure S1).

Table 5. Multivariate Analysis of Influence of CrCl and TTR on Events

	Thromboembolism		Major hemorrhage		All-cause death		Composite event*
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
CrCl <30 mL/min**	1.68 (0.41–6.85)	0.473	0.91 (0.35–2.35)	0.839	5.32 (1.56–18.18)	0.008	2.03 (1.10–3.76)	0.024
CrCl 30–49.9 mL/min**	1.61 (0.47–5.54)	0.451	0.69 (0.31–1.52)	0.352	2.59 (0.79–8.53)	0.118	1.27 (0.72–2.23)	0.408
CrCl 50–79.9 mL/min**	1.66 (0.51–5.48)	0.402	0.48 (0.22–1.03)	0.058	1.22 (0.37–4.07)	0.745	0.86 (0.48–1.50)	0.597
TTR <65%***	2.26 (1.37–3.72)	0.001	1.16 (0.72–1.87)	0.554	1.60 (1.07–2.38)	0.022	1.58 (1.22–2.04)	0.001
Heart failure	0.91 (0.52–1.57)	0.726	1.24 (0.76–2.01)	0.392	2.54 (1.66–3.90)	<0.001	1.54 (1.18–2.01)	0.002
Hypertension	0.89 (0.53–1.49)	0.649	1.57 (0.92–2.67)	0.099	0.67 (0.45–1.00)	0.050	0.93 (0.71–1.21)	0.572
Age ≥75 years	1.46 (0.83–2.60)	0.193	1.89 (1.07–3.32)	0.027	1.74 (1.03–2.93)	0.039	1.69 (1.23–2.32)	0.001
Diabetes mellitus	1.34 (0.75–2.41)	0.320	1.06 (0.61–1.81)	0.846	1.31 (0.84–2.05)	0.237	1.22 (0.91–1.64)	0.192
Stroke/TIA	1.37 (0.74–2.55)	0.323	1.44 (0.84–2.46)	0.189	2.04 (1.31–3.18)	0.002	1.64 (1.22–2.21)	0.001
CAD	1.26 (0.60–2.65)	0.537	1.09 (0.58–2.08)	0.786	1.48 (0.90–2.44)	0.126	1.32 (0.93–1.86)	0.122
Female	0.94 (0.54–1.61)	0.806	0.54 (0.31–0.93)	0.027	0.47 (0.30–0.76)	0.002	0.60 (0.44–0.81)	0.001
Antiplatelet use	0.74 (0.39–1.40)	0.354	1.26 (0.74–2.13)	0.394	1.00 (0.63–1.56)	0.991	1.00 (0.74–1.35)	0.984
Interaction between CrCl and TTR		0.103		0.248		0.012		0.003

*Thromboembolism, major hemorrhage, and all-cause death; **vs. CrCl ≥80 mL/min; ***vs. TTR ≥65%. Explanatory variables were components of CHADS₂ score (heart failure, hypertension, age ≥75 years, diabetes mellitus, and history of stroke or transient ischemic attack), CAD, female sex, and antiplatelet use. HR, hazard ratio. Other abbreviations as in Tables 1–3.

Discussion

Major Findings

The major findings of the present study were as follows. First, although baseline INR values were comparable, TTR values were lower in the groups with lower CrCl values. CrCl <30 mL/min was independently associated with lower TTR values (<65%). Second, TTR values <65% were independently associated with an increased risk of thromboembolic events, but CrCl values were not. By contrast, both TTR values <65% and CrCl values <30 mL/min were independently associated with an increased rate of all-cause death and the composite event.

Renal Dysfunction and Anticoagulation Control With Warfarin

Patients with chronic kidney disease or renal dysfunction may require lower warfarin doses,^8,9 and have worse anticoagulation control.^9–11 Our results were consistent with those previous studies,^9–11 but not with our own previous result,¹⁶ which showed TTR values were lower in patients with CrCl ≥80 mL/min compared with those with CrCl <30 mL/min. This could be explained by the inclusion of patients aged <70 years in our previous study.¹⁶ Japanese physicians tend to select lower INR values of 1.6–2.6 for AF patients regardless of their age,¹⁹ even though the Japanese guidelines indicate target INR values of 2.0–3.0 for patients aged <70 years.¹⁷ This could have resulted in the lower TTR values in the CrCl ≥80 mL/min group in our previous subanalysis in which the target INR values of 2.0–3.0 were used to calculate TTR values in younger patients,¹⁶ which has been shown by other Japanese investigators.²⁸

Szummer et al identified independent predictors for worse TTR, including lower estimated glomerular filtration rate (eGFR), age, heart failure, aspirin use, and others,¹¹ a finding that supports our results. Several possible mechanisms have been proposed for poor warfarin control in patients with renal dysfunction,⁹ including changes in non-renal drug clearance, protein binding, and drug volume distribution and downregulation of CYP-450 metabolism. Kleinow et al indicated that warfarin doses required for an adjusted INR control were smaller in patients with chronic kidney disease compared with matched controls without the disease.⁹ In our patients, daily doses of warfarin were smaller in the CrCl <30 mL/min group compared with the other CrCl groups, although baseline INR values were comparable among the 4 groups. The difference in the daily warfarin doses could be attributed, at least in part, to differences in body weight among the 4 groups (Table 2).

Relationships Among Renal Dysfunction, Warfarin Control and Outcomes

Previous studies showed AF patients with renal dysfunction were at high risk of thromboembolism, major hemorrhage, and all-cause death.^3–7,28,29 Possible mechanisms have been proposed as causes of the increased risk in these patients,⁶ and poor warfarin control, which is frequently associated with renal dysfunction,^9–11 could be one of them, as shown in the present analysis. A recent Danish cohort study showed that patients with renal dysfunction had lower TTR values, which was associated with higher rates of major hemorrhage, stroke, and thromboembolism particularly among those with eGFR of 30–60 mL/min/1.73 m².¹⁰ A Swedish study also found similar results: eGFR, TTR, age, and other variables emerged as independent predictors of composite endpoints of intracranial hemorrhage, cerebral infarction, myocardial infarction, and all-cause death.¹¹ In the present analysis, a TTR value <65% was independently associated with thromboembolism and all-cause death, a finding consistent with previous studies,^22,30 but not with major hemorrhage. However, the CrCl value was not associated with thromboembolism as in other previous studies.^31–33 Of note, higher TTR values (≥65%) need to be maintained for prevention of events in NVAF patients, particularly in those with CrCl values ≥30 mL/min (Figure, Figure S1) as reported previously.¹⁰

Study Limitations

First, this subanalysis was a post hoc analysis of an observational study and was therefore hypothesis-generating in nature. Mechanisms underlying the relationship between CrCl and TTR values were not determined. Second, patients aged <70 years were not included in the present analysis, and therefore only 38% of patients from the original 7,406 NVAF patients with follow-up data constituted the present subanalysis cohort. This hampered the present results. Third, Japanese guidelines¹⁷ recommend lower target INR values (i.e., 1.6–2.6) for NVAF patients aged ≥70 years. Therefore, the present results cannot be extrapolated to NVAF patients in other countries where different target INR values are recommended.¹⁸ Fourth, CrCl values were obtained at baseline, and serial changes in CrCl values over the follow-up period were not determined. The actual number of patients under hemodialysis was not clear, but 33 patients had CrCl values <15 mL/min at baseline.

Conclusions

The quality of anticoagulation control with warfarin worsened together with a decrease in CrCl values among elderly Japanese patients with NVAF. Lower TTR values were associated with an increased rate of thromboembolism, but lower CrCl values were not. By contrast, lower TTR values and lower CrCl values were independently associated with an increased rate of all-cause death and a composite event. Careful control of anticoagulation with warfarin may ensure better prognosis of Japanese NVAF patients with renal dysfunction.

Acknowledgments

A list of the participating cardiologists is included in references 19 and 20.

The J-RHYTHM Registry was supported by a grant from the Japan Heart Foundation (No. 12080025), Tokyo, Japan.

Disclosures

The following authors may have potential conflicts of interest: H.I. has received remuneration from Daiichi-Sankyo, Bayer Healthcare, Bristol-Myers Squibb, and Boehringer Ingelheim; K.O. has received remuneration from Boehringer Ingelheim, Bayer Healthcare, and Daiichi-Sankyo; T.Y. has received research funding from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Daiichi-Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, and Eisai; H.O. has served on the data monitoring board of trials sponsored by Daiichi-Sankyo; and H.A. has received remuneration from Daiichi-Sankyo.

Supplementary Files

Supplementary File 1

Figure S1. Effects of renal function and warfarin control on incidence rates of the composite events.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0242

References

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