Methods

We recruited consecutive patients with permanent or paroxysmal AF receiving oral anticoagulation with acenocoumarol from our outpatient anticoagulation clinic. To homogenize the cohort of patients, all patients had had an international normalized ratio of 2.0 to 3.0 during the previous 6 months of clinic visits. Patients with prosthetic heart valves, acute coronary syndrome, stroke (ischemic or embolic), valvular AF, or any hemodynamic instability and patients who had had a hospital admission or had undergone a surgical intervention in the preceding 6 months were excluded from the present study. The patients’ complete medical history was recorded. Follow-up was performed through visits to the anticoagulation clinic.

The baseline stroke risk was assessed using the CHADS ₂ score (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and previous Stroke or transient ischemic attack [doubled]) and CHA ₂ DS ₂ -VASc score (Cardiac failure or dysfunction, Hypertension, Age ≥75 years [doubled], Diabetes, Stroke [doubled]–Vascular disease, Age 65 to 74 years, and Sex category [female]), as described in recent guidelines. The HAS-BLED bleeding risk score (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [age ≥65 years], Drugs/alcohol concomitantly) was calculated as a measure of baseline bleeding risk. The presence of each factor adds 1 point. Using our inclusion criteria at study entry, the labile international normalized ratio was quantified as 0 in every patient.

The follow-up examinations were performed at our outpatient clinics. Adverse cardiovascular end points (mainly thromboembolic) were defined as stroke or transient ischemic attack, peripheral embolism, acute coronary syndrome, acute heart failure, and cardiac death. Bleeding events were assessed according to the 2005 International Society on Thrombosis and Haemostasis criteria. Bleeding events included fatal bleeding and symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a decrease in hemoglobin level of ≥20 g/L (≥1.24 mmol/L) or leading to the transfusion of ≥2 U of whole blood or red blood cells. Finally, we recorded all-cause mortality and whether the cause of death was secondary to a cardiovascular end point (stroke or transient ischemic attack, peripheral embolism, acute coronary syndrome, acute heart failure, and cardiac death) or a hemorrhagic event.

At study entry, the serum creatinine levels were recorded and the estimated glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease equation: eGFR (mL/min/1.73 m ² ) × 186 × [serum creatinine (mg/dl)] ^−1.154 × (age) ^−0.203 × (0.742 if female) × (1.212 if black). The patients were classified into 4 kidney function groups according to the eGFR values: severe chronic kidney disease (CKD), eGFR <30 ml/min/1.73 m ² ; moderate CKD, eGFR 30 to <60 ml/min/1.73 m ² ; mild CKD, eGFR 60 to <90 ml/min/1.73 m ² ; and normal renal function, eGFR ≥90 ml/min/1.73 m ² .

We assess the longitudinal change in eGFR in our patients using a new blood test after 2 years of follow-up. We also determined the serum creatinine levels and calculated the eGFR using the Modification of Diet in Renal Disease equation. We defined a significant deterioration in renal function during the follow-up period as a decrease in eGFR of >10 ml/min/1.73 m ² . All patients whose renal function was recorded 2 years after baseline were still taking anticoagulation therapy.

Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Continuous variables are presented as the mean ± SD or median and interquartile range, as appropriate, and categorical variables as percentages. Cox models were used to determine the associations between eGFR and cardiovascular events, bleeding, and mortality. The independent effect of clinical variables on prognosis was calculated using a Cox proportional hazards regression model, incorporating in the multivariate model only those values with a p value <0.15 on univariate analysis.

We explored the variables associated with significant impairment in renal function during the follow-up period (decrease of >10 ml/min/1.73 m ² in the calculated eGFR). We also explored the variables associated with development of severe CKD (eGFR <30 ml/min/1.73 m ² ). The independent effect of different variables on renal function impairment was calculated using multivariate logistic regression analysis, incorporating in the multivariate model only those values with p <0.15 on univariate analysis. A p value <0.05 was accepted as statistically significant. Statistical analysis was performed using SPSS, version 15.0, for Windows (SPSS, Chicago, Illinois).

Results

We included 978 patients in the present study. Their demographic and clinical data are listed in Table 1 . The median follow-up period was 875 days (interquartile range 706 to 1,059). During the follow-up period, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) were acute coronary syndrome, and 32 (1.37%/year) were acute heart failure. During the same period, 81 patients (3.46%/year) presented with a hemorrhagic event. Of these, 16 were intracranial hemorrhages (0.68%/year). A total of 102 patients (4.35%/year) died during the follow-up period, 31 (1.32%/year) from a thrombotic event and 8 (0.34%/year) from a hemorrhagic event.

The clinical characteristics associated with an eGFR <60 ml/min/1.73 m ² are listed in Table 2 . Decreased renal function was independently associated with female gender, age >75 years, and heart failure (all p <0.001). Also, both CHADS ₂ and CHA ₂ DS ₂ -VASc scores were associated with decreased renal function.

On univariate analysis, eGFR (as a categorical variable, per 30 ml/min/1.73 m ² decrease) was significantly associated with thrombotic/vascular events (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.11 to 1.83, p = 0.006), bleeding (HR 1.44, 95% CI 1.08 to 1.94, p = 0.015), and mortality (HR 1.47, 95% CI 1.13 to 1.91, p = 0.004). After adjusting for “high-risk” score categorization (i.e., CHA ₂ DS ₂ -VASc score ≥2 for vascular/thrombotic and mortality and HAS-BLED score ≥3 for bleeding), the adjusted HR (per 30 ml/min/1.73 m ² decrease) for thrombotic/vascular events was 1.37 (95% CI 1.07 to 1.76, p = 0.012), for mortality was 1.42 (95% CI 1.09 to 1.84, p = 0.009), and for bleeding was 1.34 (95% CI 1.00 to 1.80, p = 0.046).

We recorded the changes in eGFR during follow-up of 886 patients (90.6%; 435 men [49%]; median age 75 years, interquartile range 70 to 80). A total of 450 patients (51%) were categorized as having mild CKD (eGFR 60 to <90 ml/min/1.73 m ² , CKD stage 2), 247 patients (28%) had moderate CKD (eGFR 30 to <60 ml/min/1.73 m ² , stage 3), and 23 patients (2.6%) had severe CKD (<30 ml/min/1.73 m ² , stage 4).

After excluding those patients (n = 23) with severe renal impairment at study entry (<30 ml/min/1.73 m ² ), 863 patients were included as the study population. Of these patients, 181 (21%) experienced a reduction in the eGFR of ≥10 ml/min/1.73 m ² at 2 years. Of these 181 patients, 69 (38%) had had normal renal function at entry, 86 (48%) had had mild CKD, and 26 (14%) had had moderate CKD. A total of 58 patients had an eGFR reduction of ≥30 ml/min/1.73 m ² . Of the 21 patients with “severe renal impairment” at study entry, 5 died during follow-up, and in 9, their renal function status improved to “moderate renal impairment.”

A total of 23 patients (2.70%) developed severe CKD (<30 ml/min/1.73 m ² , stage 4). Of these 23 patients, 1 had a normal renal function at entry, 3 had mild CKD, and 19 had moderate CKD at entry. Thus, after 2 years, of the 863 patients with a baseline eGFR of ≥30 ml/min/1.73 m ² , 397 (41.8%) had mild CKD, 229 (24.1%) had moderate CKD, and 23 (2.4%) had severe CKD ( Figure 1 ). The variables associated with the development of severe renal impairment are listed in Table 3 .

Changes in eGFR from baseline to 2-year follow-up measurement.

Table 3

Clinical characteristics associated with development of severe kidney disease

Variable	Univariate Analysis			Multivariate Analysis
	OR	95% CI	p Value	OR	95% CI	p Value
Female gender	1.87	0.78–4.47	0.156
Age ≥75 yrs	1.86	0.76–4.57	0.175
Hypertension	1.00	0.34–3.00	0.989
Diabetes mellitus	2.40	1.04–5.55	0.041	1.88	0.78–4.55	0.161
Stroke	1.25	0.46–3.41	0.667
Heart failure	5.18	2.02–13.28	0.001	3.58	1.36–9.42	0.010
Coronary heart disease	1.95	0.79–4.82	0.149	1. 83	0.53–3.62	0.510
Estimated glomerular filtration rate (ml/min/1.73 m 2 )	7.77 ∗	3.00–20.10	<0.001	6.34 ∗	2.44–16.50	<0.001
CHADS 2 score	1.63	1.19–2.23	0.003
CHA 2 DS 2 -VASc score	1.50	1.16–1.93	0.002

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