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1

A prospective study of estimated glomerular filtration rate and outcomes in

patients with atrial fibrillation: The Loire Valley Atrial Fibrillation Project

Amitava Banerjee MPH DPhil1 [email protected]

Laurent Fauchier MD PhD4 [email protected]

Patrick Vourc'h PhD3 [email protected]

Christian R. Andres MD, PhD3

[email protected]

Sophie Taillandier MD4

[email protected]

Jean Michel Halimi* MD PhD2

[email protected].

Gregory Y. H. Lip* MD1 [email protected]

[*joint senior authors]

1 University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18

7QH, UK; 2Service de Nephrologie-Immunologie Clinique, Hðpital Bretonneau and Université

François Rabelais, Tours, France; 3Laboratoire de Biochimie et Biologie moléculaire, Hôpital

Bretonneau, Centre Hospitalier régional et Universitaire de Tours; 4

Service de Cardiologie, Pôle

Coeur Thorax Vasculaire, Centre Hospitalier, Universitaire Trousseau et Faculté de Médecine,

Université François Rabelais, Tours, France

Corresponding author

Prof GYH Lip ([email protected]), University of Birmingham Centre for Cardiovascular

Sciences, City Hospital, Birmingham B18 7QH, UK

Running title: Estimated glomerular filtration rate in patients with AF

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Abstract

Background: Patients with chronic kidney disease (CKD) are more likely to develop atrial

fibrillation(AF) than individuals with normal renal function, and are more likely to suffer ischaemic

stroke(IS)/thromboembolism(TE). No prior study has considered the impact of eGFR on bleeding.

We investigated the relationship of eGFR to IS/TE, mortality and bleeding in an AF population,

unrestricted by age or comorbidity.

Methods: Patients with non-valvular AF (NVAF) were stratified into five categories according to

eGFR(ml/min/1.73 m2): ≥90,60-89,30-59,15-29 and <15, analysing risk factors, all-cause mortality,

bleeding and IS/TE. Of 8962 eligible individuals, 5912 had NVAF and available serum creatinine

data, with 14499 patient-years of follow-up.

Results: In non-anticoagulated and anticoagulated individuals, the incidence rates of IS/TE were

7.4 and 7.2 per 1000 person-years, respectively. Rates of all-cause mortality were 13.4 and 9.4 per

1000 person-years, respectively, and of major bleeding, 6.2 and 9.0 per 1000 person-years,

respectively.

Rates increased with decreasing eGFR with IS/TE rates being lower in individuals receiving OAC.

eGFR was not an independent predictor of IS/TE on multivariate analyses. When the benefit of IS

reduction is balanced against the increased risk of haemorrhagic stroke, the net clinical benefit

(NCB) was clearly positive in favour of OAC use.

Conclusion: Incidence rates of IS/TE, mortality and bleeding increased with reducing eGFR, across

the whole range of renal function. OAC use was associated with a lower incidence of IS/TE and

mortality at 1 year, compared with non-anticoagulated individuals in all categories of renal function

as measured by eGFR. The NCB balancing IS against serious bleeding was positive, in favour of

OAC use amongst patients with renal impairment.

Key words:

estimated glomerular filtration rate, atrial fibrillation, stroke, bleeding, renal impairment, survival

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Abbreviations and Acronyms

NVAF Non-valvular atrial fibrillation

TE Thromboembolism

IS Ischaemic stroke

CHADS2 Acronym for Congestive heart failure, Hypertension, Age ≥75 years,

Diabetes, previous Stroke

CHA2DS2-VASc Acronym for Congestive heart failure, Hypertension, Age ≥75 years,

Diabetes, previous Stroke, Vascular disease, Age 65-74 years, Sex

category (female)

HAS-BLED Hypertension, Abnormal renal/liver function, Stroke, Bleeding history

or predisposition, Labile international normalized ratio, Elderly (> 65

years), Drugs/alcohol concomitantly

VKA Vitamin K antagonist

OAC Oral anticoagulation

eGFR Estimated glomerular filtration rate

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Introduction

Impairment of renal function and atrial fibrillation (AF) are both independently associated with

poor cardiovascular outcomes and all-cause mortality, presenting a growing global burden of

disease1-12

. Moreover, AF and chronic kidney disease (CKD) share several risk factors, including

age, hypertension, history of vascular disease and diabetes mellitus. Thus, improved understanding

of the associations between renal function and AF may lead to new approaches in risk stratification,

management and prevention.

Individuals with CKD are more likely to develop AF13-14

, ischaemic stroke(IS) and

thromboembolism(TE)15

than patients with normal renal function. In a large prospective study of

132,372 Danish individuals with AF, where 3587 individuals had CKD, the latter was associated

with increased risk of IS/TE and bleeding16

, thus confirming observations of previous smaller

studies17-21

. However, the study by Olesen et al16

was a nationwide registry cohort, which only

categorised patients as “no renal disease”, “non-end stage CKD” and “renal replacement therapy”.

In clinical practice, renal function is quantified by urinary creatinine clearance or by the estimated

glomerular filtration rate (eGFR)22-24

. Only two previous studies have considered the association

between eGFR and stroke/TE15, 25

, including only time off oral anticoagulation (OAC). No

epidemiologic studies have considered the impact of eGFR on major bleeding and all long-term

outcomes concurrently, nor included individuals with AF regardless of OAC use2-4, 16, 26

. Therefore

the balance between risk of IS/TE and bleeding has not been quantified by eGFR in a large ‘real

world’ population of individuals with AF.

Of note, renal failure is included as a dichotomous variable in risk prediction tools for bleeding but

is rarely included in guideline-recommended risk prediction tools for IS/TE21, 25, 27-30

, which is

supported by a recent analysis in our cohort which proved that renal impairment and eGFR do not

improve risk prediction of IS/TE31

. However, this analysis also showed that renal impairment was

associated with higher rates of IS/TE, compared to normal renal function. Better understanding of

the impact of renal function and eGFR on clinical outcomes in AF is required.

In a population of individuals with AF, unrestricted by age or comorbidity, we conducted the first

prospective study of renal function, as measured by eGFR, on IS/TE, mortality and bleeding.

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Among patients with renal impairment taking OAC, we also assessed the net clinical benefit (NCB)

of ischaemic stroke reduction balanced against the increased risk of haemorrhagic stroke.

Methods

The methods of the Loire Valley Atrial Fibrillation Project have been previously reported31-32

.

Extended methods for the present paper are shown in the Web-only Appendix.

Patients with non-valvular AF (NVAF) or atrial flutter diagnosed by the cardiology department

between 2000-2010 were identified (Figure 1). The CHADS228

and CHA2DS2-VASc29

scores were

calculated following the first diagnosis of AF during hospital admission, as was the HAS-BLED21

score. During follow-up, information on outcomes of TE, stroke (ischaemic or haemorrhagic),

major bleeding, and all-cause mortality were recorded by active surveillance of hospital

administrative data. The study was approved by the Review Board of the Pole Coeur Thorax

Vaisseaux from the Trousseau University Hospital in 2010 (December 7th, 2010).

Assessment of renal function

Renal failure was defined as reported history of renal failure, or baseline serum creatinine level

of >133µmol/L in men and >115µmol/L in women33

. In order to convert serum creatinine from

µmol/L to mg/dL, the former was divided by a conversion factor of 88.4. Current consensus

guidelines state that prediction equations have greater consistency and accuracy than serum

creatinine in the assessment of GFR22-24, 34-36

. In addition, prediction equations are equivalent or

better than 24-hour urine creatinine clearance in all but one study22-24, 37

. In adults, the most widely-

used and validated method for estimating GFR from serum creatinine level is the isotope dilution

mass spectrometry (IDMS)-traceable Modification of Diet in Renal Disease (MDRD) Study

equation22-24

. The laboratories where biochemical analysis of creatinine levels was conducted were

calibrated to be IDMS-traceable. The MDRD equation was preferred to the more recently validated

“CKD-Epi” equation38

because there were very few patients aged≥75 years in cohorts used to

validate this equation whereas the current study population was unrestricted by age.

eGFR = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American)

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where eGFR is the estimated glomerular filtration rate in mL/min/1.73 m2, Scr is serum creatinine

level in mg/dL. The African population in the study population was <1% and therefore no

correction factor for ethnicity was required in the MDRD calculation of eGFR.

Statistical analysis

The study population was stratified into five categories according to eGFR (in ml/min/1.73 m2),

corresponding to the stages of CKD: ≥90, 60-89, 30-59, 15-29, and <15 (Figure 1)22-24

. Since data

regarding proteinuria was not available, stage of renal impairment could not be defined. Baseline

characteristics were determined separately for the five eGFR strata, and differences were

investigated using chi-squared test for categorical covariates and Kruskal-Wallis test for continuous

covariates. Age-adjustment was performed by including age as a covariate in a logistic regression

model.

Cumulative incidence rates of IS/TE, bleeding and all-cause mortality were calculated for all

patients by eGFR category, stratifying by presence or absence of VKA therapy. Since VKA therapy

was the only form of OAC used during the study period, the terms, “VKA” and “OAC” are used

interchangeably in the analyses. Due to low numbers of patients and outcomes in the categories

with eGFR≥90 and <15 ml/min/1.73m2, rates were calculated for categories with eGFR≥60, 30-59

and <30 ml/min/1.73m2. Haemorrhagic strokes were excluded from analyses of “stroke” or

“stroke/TE”. Event rates were also calculated by age and sex categories. In each eGFR category,

Cox-proportional hazards analyses were performed to calculate 1-year survival for IS/TE, bleeding

and all-cause mortality. Bivariate analyses of event rates in different subgroups were used to

calculate hazard ratios associated with renal impairment and eGFR category.

Cox proportional-hazard regression models were constructed to investigate whether renal

impairment and eGFR were independent predictors of IS/TE. The risk associated with renal

impairment and eGFR were estimated in a univariate analysis, as well as a sex- and age-adjusted

analysis, an analysis adjusted for the risk factors included in the CHADS2 score, and a multivariate

analysis adjusted for all baseline characteristics in Table 1. All analyses were repeated by eGFR

category, and by combined stratification by renal impairment and eGFR. Further, to test whether the

results were influenced by patients initiating treatment with VKA, we performed additional

analyses excluding patients at the initiation of such treatment.

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Finally, the net clinical benefit (NCB) was calculated, as originally proposed by Singer and

colleagues39

using the formula:

Net clinical benefit (NCB) = IS rate on no treatment- IS rate on anticoagulant)-1.5(ICH rate on no

treatment- ICH rate on anticoagulant

…. where IS=ischaemic stroke and ICH=intracerebral haemorrhage, which is the most serious form

of bleeding associated with OAC use. A modified formula with “haemorrhagic stroke” instead of

“ICH” was used to calculate NCB for the different eGFR categories. The NCB is used by clinicians

and researchers as a validated method of balancing risk of ischaemic stroke against intracerebral

haemorrhage.

A two-sided p-value <0.05 was considered statistically significant.

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Results

Of 8962 eligible individuals, 5912 (66.0%) had non-valvular AF and available serum creatinine

data, allowing the eGFR to be calculated (Figure 1). Thus, 14499 patient-years of follow-up were

included in the analysis, with mean follow-up of 2.45 (SD 3.56) years. We focused on the 1-year

outcomes in our analyses.

Baseline characteristics are shown in Table 1. Individuals with eGFR<15 mL/min/1.73m2 were

older, and more likely to be female and have paroxysmal AF, compared with individuals with

eGFR>90mL/min/1.73m2. After age-adjustment, individuals with eGFR<15 mL/min/1.73 m

2 were

more likely to have hypertension, heart failure (p<0.001), diabetes mellitus (p=0.001), liver

impairment (p=0.005), pacemaker/ICD (p=0.004), smoking history (p=0.04), diuretic therapy

(p<0.001) and higher CHADS2, CHA2DS2-VASc and HAS-BLED scores (p<0.001), when

compared with individuals with eGFR>90mL/min/1.73 m2, but there were no significant differences

in rates of OAC or antithrombotic therapies.

Rates of the composite of ‘stroke and all-cause mortality’ were lower in individuals on OAC,

compared with those individuals not on OAC. In non-anticoagulated and anticoagulated individuals,

rates of IS/TE were 7.4 (95% CI 6.3-8.6) and 7.2 (6.3-8.2) per 1000 person years, respectively.

Incidence rates of all-cause mortality were 13.4 (12.0-15.0) and 9.4 (8.3-10.5), respectively, and of

major bleeding were 6.2 (5.2-7.3) and 9.0 (8.0-10.1) per 1000 person years, respectively. Rates of

all events increased with decreasing eGFR, regardless of OAC therapy (Table 2). Bleeding rates

were higher in individuals on OAC, compared with non-anticoagulated individuals.

VKA was associated with approximately 50% relative risk reduction for stroke/TE/all-cause

mortality and all-cause mortality in all eGFR categories (Table 2). There was a trend towards

relative risk reduction for stroke and IS/TE with VKA, but this was not statistically significant. In

patients with eGFR≥60 mL/min/1.73 m2, VKA was associated with higher risk of bleeding (RR

1.57, 1.16-2.14), but there was no statistically significant increase in bleeding risk in other eGFR

categories (Table 2). After stratification by age and sex, the reduction in eGFR was associated with

increased rates of all-cause mortality, IS/TE and bleeding in men and women and in all age groups

(figure 2).

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Table 3 shows the results from the Cox regression analyses. Neither renal impairment nor eGFR

were independent predictors of IS/TE in AF at 1 year follow-up in univariate or multivariate

analyses, after adjustment for age, sex, CHADS2 risk factors or baseline characteristics. Table 4

shows analogous results from Cox regression analyses after excluding patients on vitamin K

antagonists at baseline (n=3592; 60.8%). As a categoric variable, eGFR was an independent

predictor for IS/TE on univariate analysis (HR 1.80;1.27-2.55), but not after adjustment for age,

sex, CHADS2 risk factors or baseline characteristics at 1 year follow-up.

When the benefit of ischaemic stroke reduction is balanced against the increased risk of

haemorrhagic stroke amongst patients with renal impairment, the net clinical benefit (NCB) was

clearly positive in favour of VKA use, for example, in individuals with a eGFR=30-59,

NCB=2.06(95%CI 1.40-2.88), as well as those with eGFR<30, NCB=6.69(3.27-12.78).

Renal failure vs normal renal function

In the presence of VKA, rates of IS/TE were 6.2% and 3.9% at 1 year in individuals with renal

failure and with normal renal function respectively. The corresponding rates of all-cause mortality

were 10.8% and 3.4% at 1 year, and rates of bleeding were 9.3% and 4.5% at 1 year respectively

(Figure 3). In non-anticoagulated individuals, at 1 year, rates of IS/TE, all-cause mortality and

bleeding were 5.8% and 5.1%, 18.9% and 9.6%, and 9.4% and 3.9% with renal failure and with

normal renal function respectively (Figure 3).

Individuals with eGFR≥60mL/min/1.73m2 compared with eGFR <30 mL/min/1.73m

2

Rates of IS/TE were 3.3% and 7.0% at 1 year in individuals with eGFR≥60mL/min/1.73m2and with

eGFR <30 mL/min/1.73m2 respectively. At 1 year, the corresponding rates of all-cause mortality

were 4.2% and 17.6%, and the rates of bleeding were 3.8% and 10.0% (Figure 3).

VKA was associated with reduced hazard of mortality, increased hazard of bleeding and a trend

towards reduced risk of IS/TE, regardless of renal function (Figure 3).

In both anticoagulated and non-anticoagulated individuals, incidence rates of IS/TE, mortality and

bleeding increased with reducing eGFR. In non-anticoagulated individuals with renal failure, the

risk of mortality was 4-fold greater than in anti-coagulated individuals with normal renal function

(HR 3.65, 95%CI 2.86-4.66) (Figure 4).

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Discussion

This is the first prospective study of the impact of renal function, as measured by eGFR, on IS/TE,

mortality and bleeding in the same population of individuals with AF, with four major findings.

First, in AF patients, renal failure and reduced eGFR were associated with a more severe risk factor

profile, higher rates of permanent AF, higher risk of IS/TE and bleeding as measured by validated

risk stratification schemes and worse outcomes. Second, individuals receiving OAC had lower

incidence of IS/TE and mortality, compared with non-anticoagulated individuals in all categories of

renal function measured by eGFR. Indeed, the net clinical benefit (NCB) balancing ischaemic

stroke reduction against the increased risk of haemorrhagic stroke was clearly positive in favour of

OAC use amongst patients with renal impairment. Third, rates of IS/TE, mortality and bleeding

increased with reducing eGFR, regardless of gender, age or OAC therapy. Fourth, renal impairment,

whether as a dichotomous variable or measured by eGFR, was not a significant predictor of IS/TE

at 1 year after adjustment for baseline characteristics.

The 1-year risks for stroke/TE and mortality were significantly increased by renal failure and

absence of OAC. When eGFR was <30mL/min/1.73m2, 1-year mortality was 17.6%. Our data

confirm that in addition to its growing global burden8-10

, the outcomes of AF are at least as severe

as in contemporary data for atherosclerotic vascular diseases40

.

The rates of IS/TE in non-anticoagulated individuals in this population (12.0 and 14.3 per 1000

person years with eGFR stage 30-59 and <30 mL/min/1.73m2 respectively) were lower than the

ATRIA study (4.2 per 100 person years in patients with eGFR <45mL/min/1.73 m2)15

. Although the

ATRIA cohort and our study population have similar comorbidities and similar rates of OAC, the

older age of patients in the former study may explain the higher IS/TE rates. Our data suggest that

the association between low eGFR and IS/TE is explained by confounding since there was no

independent association after adjustment for baseline characteristics, and moreover, we have

already shown that eGFR does not add incremental value to risk prediction in IS/TE. Indeed, renal

impairement is commonly associated with many of the individual components of CHADS2 and

CHA2DS2-VASc scores and thus, our observation that neither renal impairment nor eGFR were

independent predictors of IS/TE in AF is perhaps unsurprising. Two recent analyses found that

renal function (as measured by eGFR) was independently predictive of IS/TE25,41

. However, our

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study is a contemporary ‘real-world’ population whilst the ATRIA cohort stopped recruiting in

2003 and therefore may not represent contemporary clinical practice in AF populations.

In this study, individuals with renal failure and AF, as measured by eGFR were less likely to be on

OAC than individuals with normal renal function (Table 1). Current consensus guidelines do not

recommend routine OAC in patients on haemodialysis (which may explain the low rates of OAC in

patients with renal impairment in our population) although limited data already suggest a reduction

in stroke/TE with OAC in patients with CKD42-45

.

Our observations illustrate the high bleeding risk associated with increasing renal impairment in a

series of patients with one of the longest follow-up periods in the literature to-date. Indeed, the

latter may have implications for future risk stratification schemes for major bleeding which

currently classify renal failure as a dichotomous variable21

. Trials of OAC (including novel

anticoagulants) are urgently required in patients with renal impairment in order to establish the

balance of efficacy vs safety of OAC in this patient group, especially because the majority of AF

trials have excluded patients with CKD and most do not even analyse the effect of renal function22,

45-50. However, the moderate-high renal clearance of most novel anticoagulants probably limits their

use in moderate/severe renal impairment, although the oral Factor Xa inhibitor, betrixaban is

minimally renally cleared and is the only novel agent that could be studied in individuals with

severe renal impairment51

.

In our NCB analysis balancing ischaemic stroke reduction against the increased risk of

haemorrhagic stroke amongst patients with renal impairment, there was a positive NCB in favour of

OAC use. The original NCB analysis for warfarin by Singer and colleagues39

in patients with AF

showed greatest benefit in patients with the highest untreated risk for stroke. The NCB of warfarin

may be greatest in patients with highest bleeding risk who also have high stroke risk (as measured

by validated risk stratification scoring systems)52

, and extrapolation of available clinical trial data

suggests the same trends for novel anticoagulants53

. In the present study, we clearly show for the

first time that warfarin may have greatest NCB, when balancing ischaemic stroke against

haemorrhagic stroke, in individuals with AF and renal failure.

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Study limitations.

This study is based on a ‘real world’ registry with inherent limitations of diagnostic coding and case

ascertainment, as previously reported31, 32

. Despite stratification and adjustment for several risk

factors, the non-randomized design leaves a risk of residual confounding factors, but as already

stated, the majority of randomised trials to-date in AF patients have excluded analyses of the effect

of renal function. If a resident moved away from the area or died or had a stroke diagnosed

elsewhere, information on the event was not available. However, the relatively high number of

deaths in our study suggests a high proportion of ascertainment of events. The study population was

hospital-based and therefore may not be representative of all patients with AF, many of whom are

not hospitalized for their arrhythmia. The study was not ethnically diverse and our findings may not

be generalisable to other populations.

In the randomised trials, anticoagulation reduces stroke (by 64%) and all cause mortality (by

26%)54

. In our study, although VKA was associated with a relative risk reduction in

stroke/TE/mortality and all-cause mortality, there was not a statistically significant relative risk

reduction for ischaemic stroke, despite lower event rates in patients on VKA versus patients not on

VKA. A possible explanation may be that in such ‘real world’ registries, some recorded deaths may

be due to strokes, as not all patients had routine post mortems or detailed cerebral imaging,

therefore leading to the our findings of a higher-than-predicted risk reduction for all-cause mortality

and a non-statistically significant risk reduction for ischaemic stroke, compared with clinical trials.

The data regarding OAC use are only regarding baseline therapy and do not reflect any changes in

prescribed therapy or adherence to therapy. Also, data regarding the “time in therapeutic range”

(TTR) are not available for our study population. Our study population was a prospective cohort

design and not a randomised clinical trial, therefore, confounding by indication is a possibility55

.

However, the effect of this confounding is likely to be minimal since the individuals at highest risk

of study outcomes (based on risk prediction scores) were least likely to be taking OAC. Only

baseline creatinine measurements and eGFR calculations are available and therefore, we are unable

to comment on change or progression of renal impairment, nor the need for renal replacement

therapy. We used a categoric eGFR variable analysis as this would be more useful in terms of

incorporating eGFR into a risk prediction score; there was no appreciable difference with eGFR

analysed as a continuous variable. However, eGFR is probably the most important indicator of renal

function to take into account, since OAC doses are usually lower in patients with CKD than in those

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without CKD and changes are more often necessary in this situation56

. Finally, the number of

individuals with eGFR<30 mL/min/1.73 m2 in the study population was small (as were the number

on dialysis) and therefore, the statistical power of analysis in this subgroup may be limited.

Conclusions

Renal impairment is associated with poor outcomes at 1 year in individuals with NVAF across the

whole range of renal function, as measured by eGFR. OAC use was associated with a lower

incidence of IS/TE and mortality, compared with non-anticoagulated individuals in all categories of

renal function as measured by eGFR. Indeed, the NCB balancing ischaemic stroke against major

bleeding was positive, in favour of OAC use amongst patients with renal impairment, suggesting

that bleeding risk is not the most important variable in stroke prevention treatment decisions in

these individuals. Therefore, full anticoagulation is recommended in patients with at least moderate

renal impairment, with improved attention to good quality INR control (as reflected by a high time

in therapeutic range, which is associated with lower event rates57

). Whilst eGFR was not an

independent predictor of IS/TE in patients with AF, these patients are still ‘high risk’ and regular

checks on eGFR would be recommended, especially since normal or mild renal impairment at

baseline does not preclude some patients deteriorating to severe renal impairment58

. These

observations have implications for future risk prediction tools of outcomes in NVAF as well as

future clinical trials.

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Acknowledgments

Author Contributions - AB, GYHL, and LF contributed to the study conception and design. LF, ST,

JMH and PV made the primary contribution to data collection. AB performed the analyses and

produced the initial manuscript. All authors contributed to interpretation of results, revising the

manuscript critically for important intellectual content, and all approved the final manuscript.

LF had full access to all the data in the study and takes responsibility for the integrity of the data

and the accuracy of the data analysis.

All authors – no conflicts of interest pertaining directly to this paper. No funding (commercial/non-

commercial) was received for this study.

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References

1. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA,

Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW;

American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood

Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Kidney disease

as a risk factor for development of cardiovascular disease: a statement from the American

Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure

Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension

2003;42:1050-65.

2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks

of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.

3. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, Salem DN, Levey

AS, Sarnak MJ. Chronic kidney disease as a risk factor for cardiovascular disease and all-

cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol

2004;15:1307-15.

4. Coresh J, Astor B, Sarnak MJ. Evidence for increased cardiovascular disease risk in patients

with chronic kidney disease. Curr Opin Nephrol Hypertens 2004;13:73-81.

5. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease

to the global burden of major noncommunicable diseases. Kidney Int. 2011;8:1258-70.

6. McCullough K, Sharma P, Ali T, Khan I, Smith WC, Macleod A, Black C. Measuring the

population burden of chronic kidney disease: a systematic literature review of the estimated

prevalence of impaired kidney function.Nephrol Dial Transplant. 2012;27:1812-21.

7. Nugent RA, Fathima SF, Feigl AB, Chyung D.The burden of chronic kidney disease on

developing nations: a 21st century challenge in global health.Nephron Clin Pract.

2011;118:c269-77.

8. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, , Vasan RS, D'Agostino RB,

Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial

fibrillation: the Framingham Heart Study. Circulation. 2004; 110:1042-6.

9. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH Stijnen T,

Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the

Rotterdam Study. Eur Heart J 2006; 27: 949–53.

of 37


https://www.researchgate.net/publication/51714015_The_contribution_of_chronic_kidney_disease_to_the_global_burden_of_major_noncommunicable_diseases?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/51714015_The_contribution_of_chronic_kidney_disease_to_the_global_burden_of_major_noncommunicable_diseases?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/7250308_Prevalence_Incidence_and_Lifetime_risk_of_Atrial_Fibrillation_The_Rotterdam_study?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/8397391_Lifetime_Risk_for_Development_of_Atrial_Fibrillation_The_Framingham_Heart_Study?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/51686918_Measuring_the_population_burden_of_chronic_kidney_disease_a_systematic_literature_review_of_the_estimated_prevalence_of_impaired_kidney_function?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/49734961_The_Burden_of_Chronic_Kidney_Disease_on_Developing_Nations_A_21st_Century_Challenge_in_Global_Health?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/8612527_Evidence_for_increased_cardiovascular_disease_risk_in_patients_with_chronic_kidney_disease?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/8612527_Evidence_for_increased_cardiovascular_disease_risk_in_patients_with_chronic_kidney_disease?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/275546420_Chronic_Kidney_Disease_and_the_Risks_of_Death_Cardiovascular_Events_and_Hospitalization?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/275546420_Chronic_Kidney_Disease_and_the_Risks_of_Death_Cardiovascular_Events_and_Hospitalization?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

16

10. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB,

Tsang TS. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota,

1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;

114: 119–25.

11. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for

stroke: the Framingham Study. Stroke. 1991; 22: 983–88.

12. Kurth T, de Jong PE, Cook NR, Buring JE, Ridker PM. Kidney function and risk of

cardiovascular disease and mortality in women: a prospective cohort study. BMJ. 2009 Jun

29;338:b2392. doi: 10.1136/bmj.b2392.

13. Alonso A, Lopez FL, Matsushita K, Loehr LR, Agarwal SK, Chen LY, Soliman EZ, Astor

BC, Coresh J. Chronic kidney disease is associated with the incidence of atrial fibrillation:

the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2011;123:2946-53.

14. Horio T, Iwashima Y, Kamide K, Tokudome T, Yoshihara F, Nakamura S, Kawano Y.

Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in

hypertensive patients. J Hypertens. 2010;28:1738-44.

15. Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L, Singer DE;

ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of

thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial

fibrillation (ATRIA) study. Circulation. 2009;119:1363-9.

16. Olesen JB, Lip GY, Kamper AL, Hommel K, Køber L, Lane DA, Lindhardsen J, Gislason

GH, Torp-Pedersen C. Stroke and bleeding in atrial fibrillation with chronic kidney disease.

N Engl J Med. 2012;367:625-35.

17. Nakagawa K, Hirai T, Takashima S, Fukuda N, Ohara K, Sasahara E, Taguchi Y, Dougu N,

Nozawa T, Tanaka K, Inoue H. Chronic kidney disease and CHADS(2) score independently

predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation.

Am J Cardiol. 2011;107:912-6.

18. Vázquez E, Sánchez-Perales C, Lozano C, García-Cortés MJ, Borrego F, Guzmán M, Pérez

P, Pagola C, Borrego MJ, Pérez V. Comparison of prognostic value of atrial fibrillation

versus sinus rhythm in patients on long-term hemodialysis. Am J Cardiol. 2003;92:868-71.

19. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey

GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM. Prevention of stroke and systemic

embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial

fibrillation and moderate renal impairment Eur Heart J. 2011;32:2387-94.

of 37


17

20. Abdelhafiz AH, Myint MP, Tayek JA, Wheeldon NM. Anemia, hypoalbuminemia, and

renal impairment as predictors of bleeding complications in patients receiving

anticoagulation therapy for nonvalvular atrial fibrillation: a secondary analysis. Clin Ther.

2009;31:1534-9.

21. 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;138:1093-100. Epub 2010 Mar 18.

22. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney

disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl

1):S1-266.

23. Archibald G, Bartlett W, Brown A, Christie B, Elliott A, Griffith K, Pound S, Rappaport I,

Robertson D, Semple Y, Slane P, Whitworth C, Williams B. UK consensus conference on

early chronic kidney disease. Edinburgh: Royal College of Physicians; 2007.

http://www.rcpe.ac.uk/clinical-standards/standards/UK-Consensus-Conference-on-Early-

Chronic-Kidney-Disease-Feb-2007.pdf [accessed 12 June 2013]

24. National Institute for Health and Clinical Excellence (NICE). CG73 Chronic kidney disease:

Early identification and management of chronic kidney disease in adults in primary and

secondary care. NICE clinical guidelines Issued: September 2008

25. Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey

KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA,

Califf RM; ROCKET AF Steering Committee and Investigators. Renal dysfunction as a

predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation:

validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral,

direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke

and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In

Atrial fibrillation) study cohorts. Circulation. 2013;127:224-32

26. Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention in atrial

fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol.

2011;57:1339-48.

27. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, Radford MJ.

Clinical classification schemes for predicting hemorrhage: results from the National

Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713-9.

of 37


18

28. 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; 285:2864–70.

29. 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; 137:263-72.

30. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic

stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial

Fibrillation cohort study. Eur Heart J. 2012;33:1500-10.

31. Banerjee A, Fauchier L, Vourc'h P, Andres CR, Taillandier S, Halimi JM, Lip GY. Renal

impairment and ischaemic stroke risk assessment in patients with atrial fibrillation: The

Loire Valley Atrial Fibrillation Project. J Am Coll Cardiol. 2013 Mar 21. [Epub ahead of

print]

32. Banerjee A, Taillandier S, Olesen JB, Lane DA, Lallemand B, Lip GY, Fauchier L. Ejection

fraction and outcomes in patients with atrial fibrillation and heart failure: the Loire Valley

Atrial Fibrillation Project. Eur J Heart Fail. 2012;14:295-301.

33. Couchoud C, Pozet N, Labeeuw M, Pouteil-Noble C. Screening early renal failure: cut-off

values for serum creatinine as an indicator of renal impairment. Kidney Int. 1999;55:1878-

84.

34. Van Den Noortgate NJ, Janssens WH, Delanghe JR, Afschrift MB, Lameire NH. Serum

cystatin C concentration compared with other markers of glomerular filtration rate in the old

old. J Am Geriatr Soc 2002;50:1278-82.

35. Daniel JP, Chantrel F, Offner M, Moulin B, Hannedouche T. Comparison of cystatin C,

creatinine and creatinine clearance vs. GFR for detection of renal failure in renal transplant

patients. Ren Fail 2004;26:253-7.

36. Schuck O, Gottfriedova H, Maly J, Jabor A, Stollova M, Bruzkova I, , Skibova J, Ryska M,

Spicak J, Trunecka P, Novakova J. Glomerular filtration rate assessment in individuals after

orthotopic liver transplantation based on serum cystatin C levels. Liver Transpl 2002;8:594-

9.

37. Mariat C, Alamartine E, Barthelemy JC, De Filippis JP, Thibaudin D, Berthoux P, , Laurent

B, Thibaudin L, Berthoux F. Assessing renal graft function in clinical trials: can tests

predicting glomerular filtration rate substitute for a reference method? Kidney Int

2004;65:289-97.

of 37


19

38. Botev R, Mallié JP, Wetzels JF, Couchoud C, Schück O. The clinician and estimation of

glomerular filtration rate by creatinine-based formulas: current limitations and quo vadis.

Clin J Am Soc Nephrol. 2011;6:937-50.

39. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. The

net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;

151: 297–305.

40. Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF, Lovelock CE, Redgrave JN, Bull

LM, Welch SJ, Cuthbertson FC, Binney LE, Gutnikov SA, Anslow P, Banning AP, Mant D,

Mehta Z; Oxford Vascular Study. Population-based study of event-rate, incidence, case

fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular

Study). Lancet. 2005;366:1773-83.

41. Singer DE, Chang Y, Borowsky LH, Fang MC, Pomernacki NK, Udaltsova N, Reynolds K,

Go AS. A New Risk Scheme to Predict Ischemic Stroke and Other Thromboembolism in

Atrial Fibrillation: The ATRIA Study Stroke Risk Score. J Am Heart Assoc. 2013;2:

e000250.

42. Herzog CA, Asinger RW, Berger AK, Charytan DM, Díez J, Hart RG, Eckardt KU, Kasiske

BL, McCullough PA, Passman RS, DeLoach SS, Pun PH, Ritz E. Cardiovascular disease in

chronic kidney disease. A clinical update from Kidney Disease: Improving Global

Outcomes (KDIGO). Kidney Int. 2011;80:572-86.

43. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with

moderate chronic kidney disease.Clin J Am Soc Nephrol 2011;6(11):2599-604). Clin J Am

Soc Nephrol. 2011;6:2599-604.

44. Wizemann V, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW,

Robinson BM. Atrial fibrillation in hemodialysis patients: clinical features and associations

with anticoagulant therapy. Kidney Int. 2010;77:1098-106.

45. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin

initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc

Nephrol. 2011;6:2662-8.

46. Morocutti C, Amabile G, Fattapposta F, Nicolosi A, Matteoli S, Trappolini M, Cataldo G,

Milanesi G, Lavezzari M, Pamparana F, Coccheri S. Indobufen versus warfarin in the

secondary prevention of major vascular events in nonrheumatic atrial fibrillation. SIFA

(Studio Italiano Fibrillazione Atriale) Investigators. Stroke. 1997;28:1015-21.

of 37


https://www.researchgate.net/publication/51635633_Warfarin_in_Atrial_Fibrillation_Patients_with_Moderate_Chronic_Kidney_Disease?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/7470833_Population-based_study_of_event-rate_incidence_case_fatality_and_mortality_for_all_acute_vascular_events_in_all_arterial_territories_Oxford_Vascular_Study?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==





https://www.researchgate.net/publication/40870198_Atrial_fibrillation_in_hemodialysis_patients_Clinical_features_and_associations_with_anticoagulant_therapy?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/50939950_The_Clinician_and_Estimation_of_Glomerular_Filtration_Rate_by_Creatinine-based_Formulas_Current_Limitations_and_Quo_Vadis?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/50939950_The_Clinician_and_Estimation_of_Glomerular_Filtration_Rate_by_Creatinine-based_Formulas_Current_Limitations_and_Quo_Vadis?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/51487056_Cardiovascular_disease_in_chronic_kidney_disease_A_clinical_update_from_Kidney_Disease_Improving_Global_Outcomes_KDIGO?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




https://www.researchgate.net/publication/51681811_Effectiveness_and_Safety_of_Warfarin_Initiation_in_Older_Hemodialysis_Patients_with_Incident_Atrial_Fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/239941624_A_New_Risk_Scheme_to_Predict_Ischemic_Stroke_and_Other_Thromboembolism_in_Atrial_Fibrillation_The_ATRIA_Study_Stroke_Risk_Score?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




https://www.researchgate.net/publication/26780659_The_Net_Clinical_Benefit_of_Warfarin_Anticoagulation_in_Atrial_Fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/252321741_Indobufen_Versus_Warfarin_in_the_Secondary_Prevention_of_Major_Vascular_Events_in_Nonrheumatic_Atrial_Fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




20

47. Hellemons BS, Langenberg M, Lodder J, Vermeer F, Schouten HJ, Lemmens TG, van Ree

JW, Knottnerus JA. Primary prevention of arterial thromboembolism in nonrheumatic atrial

fibrillation: the PATAF trial study design. Control Clin Trials. 1999;20:386-93.

48. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly

PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius

H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators.

Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-

51.

49. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR,

Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia

D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J,

Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW,

Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin

in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.

50. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL,

Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf

RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial

fibrillation. N Engl J Med. 2011;365:883-91.

51. Ahrens I, Peter K, Lip GY, Bode C. Development and clinical applications of novel oral

anticoagulants. Part II. Drugs under clinical investigation. Discov Med. 2012;13:445-50.

52. Olesen JB, Lip GY, Lindhardsen J, Lane DA, Ahlehoff O, Hansen ML, Raunsø J, Tolstrup

JS, Hansen PR, Gislason GH, Torp-Pedersen C. Risks of thromboembolism and bleeding

with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis

using a 'real world' nationwide cohort study. Thromb Haemost. 2011;106:739-49.

53. Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral

anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial

fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb

Haemost. 2012;107:584-9.

54. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in

patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-67.

55. Signorello LB, McLaughlin JK, Lipworth L, Friis S, Sørensen HT, Blot WJ. Confounding

by indication in epidemiologic studies of commonly used analgesics. Am J Ther.

2002;9:199-205.

of 37


https://www.researchgate.net/publication/51879867_Net_clinical_benefit_of_new_oral_anticoagulants_dabigatran_rivaroxaban_apixaban_versus_no_treatment_in_a_'real_world'_atrial_fibrillation_population_A_modelling_analysis_based_on_a_nationwide_cohort_s?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




https://www.researchgate.net/publication/12858372_Primary_Prevention_of_Arterial_Thromboembolism_in_Nonrheumatic_Atrial_Fibrillation_The_PATAF_trial_study_design?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/51521367_Risks_of_thromboembolism_and_bleeding_with_thromboprophylaxis_in_patients_with_atrial_fibrillation_A_net_clinical_benefit_analysis_using_a_'real_world'_nationwide_cohort_study?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




https://www.researchgate.net/publication/11425794_Confounding_by_Indication_in_Epidemiologic_Studies_of_Commonly_Used_Analgesics?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/228086754_Development_and_Clinical_Applications_of_Novel_Oral_Anticoagulants_Part_II_Drugs_Under_Clinical_Investigation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/228086754_Development_and_Clinical_Applications_of_Novel_Oral_Anticoagulants_Part_II_Drugs_Under_Clinical_Investigation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/6260169_Meta-analysis_Antithrombotic_therapy_to_prevent_stroke_in_patients_who_have_nonvalvular_atrial_fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/6260169_Meta-analysis_Antithrombotic_therapy_to_prevent_stroke_in_patients_who_have_nonvalvular_atrial_fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/40849243_Dabigatran_versus_Warfarin_in_Patients_with_Atrial_Fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

https://www.researchgate.net/publication/40849243_Dabigatran_versus_Warfarin_in_Patients_with_Atrial_Fibrillation?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==

21

56. Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, Acton RT, Allon

M. Kidney function influences warfarin responsiveness and hemorrhagic complications. J

Am Soc Nephrol. 2009;20:912-21.

57. Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality

associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost.

2011;106:968-77.

58. Roldán V, Marín F, Fernández H, Manzano-Fernández S, Gallego P, Valdés M, Vicente V,

Lip GY. Renal impairment in a "real-life" cohort of anticoagulated patients with atrial

fibrillation (implications for thromboembolism and bleeding). Am J Cardiol.

2013;111:1159-64.

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https://www.researchgate.net/publication/234823294_Renal_Impairment_in_a_Real-Life_Cohort_of_Anticoagulated_Patients_With_Atrial_Fibrillation_Implications_for_Thromboembolism_and_Bleeding?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==




https://www.researchgate.net/publication/51627127_Risks_of_stroke_and_mortality_associated_with_suboptimal_anticoagulation_in_atrial_fibrillation_patients?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



https://www.researchgate.net/publication/24023029_Kidney_Function_Influences_Warfarin_Responsiveness_and_Hemorrhagic_Complications?el=1_x_8&enrichId=rgreq-5472d031a56db3c245b659a020a14eab-XXX&enrichSource=Y292ZXJQYWdlOzI1OTM5NDg5OTtBUzoxMDM0NzczMjE2NjY1NzhAMTQwMTY4MjMyNDYzNg==



22

Table 1: Characteristics of patients with atrial fibrillation in relation to degree of renal impairment

eGFR (in ml/min/1.73 m2)

n (%) ≥90

n=284

60-89

n=2646

30-59

n=2641

15-29

n=287

<15

n=54

p-value Age-adjusted

p-value*

Mean age (SD) 52.8(21.2) 65.1(15.2) 75.9(10.5) 79.9(9.1) 76.4(11.5) <0.001 -

Female 53(18.7) 741(28.0) 1217(46.1) 158(55.1) 27(50.0) <0.001 <0.001

Mean follow-up (SD) 3.0(2.9) 2.5(3.3) 2.4(3.8) 2.1(2.0) 1.6(1.4) - -

Type of AF

Paroxysmal

Permanent

Persistent

188(66.2)

85(29.9)

11(3.9)

1604(60.6)

897(33.9)

145(5.5)

1426(54.0)

1060(40.1)

155(5.9)

146(50.9)

127(44.3)

17(4.9)

31(57.4)

20(37.0)

3(5.6)

<0.001 0.87

Comorbidities

Hypertension 75(26.4) 979(37.0) 1274(48.2) 175(61.0) 34(63.0) <0.001 <0.001

Diabetes 42(14.8) 377(14.2) 454(17.2) 81(28.2) 14(25.9) <0.001 0.001

Previous stroke 24(8.5) 173(6.5) 212(8.0) 30(10.5) 9(16.7) 0.005 0.29

Coronary artery disease 48(16.9) 728(27.5) 942(35.7) 112(39.0) 16(29.6) <0.001 0.17

Any vascular disease 57(20.1) 797(30.1) 1031(39.0) 129(44.9) 20(37.0) <0.001 0.07

Heart failure 101(35.6) 1164(44.0) 1578(59.8) 212(73.9) 43(79.6) <0.001 <0.001

Renal impairment 0(0.0) 2(0.1) 1194(45.2) 287(100.0) 54(100.0) <0.001 <0.001

Liver impairment 5(1.8) 8(0.3) 4(0.2) 1(0.3) 0(0.0) <0.001 0.005

Dyslipidaemia 40(14.1) 506(19.1) 529(20.0) 61(21.3) 12(22.2) 0.15 0.11

Smoking 52(18.3) 385(14.6) 259(9.8) 40(13.9) 8(14.8) <0.001 0.004

Pacemaker/ICD 34(12.0) 395(14.9) 537(20.3) 60(20.9) 12(22.2) <0.001 0.04

Bleeding risk factors

Previous bleeding 21(7.4) 109(4.1) 126(4.8) 20(7.0) 7(13.0) 0.001 0.47

Labile INR 7(2.5) 45(1.7) 43(1.6) 7(2.4) 2(3.7) 0.54 0.82

Anaemia 0(0.0) 13(0.5) 19(0.7) 5(1.7) 0(0.0) 0.06 0.04

NSAIDs 0(0.0) 2(0.1) 6(0.2) 0(0.0) 0(0.0) 0.53 0.59

Drugs 31(10.9) 416(15.7) 560(21.2) 64(22.3) 11(20.4) <0.001 0.44

Cancer 4(1.4) 39(1.5) 51(1.9) 8(2.8) 2(3.7) 0.30 0.76

Excessive risk of falls 3(1.1) 16(0.6) 36(1.4) 5(1.7) 3(5.6) 0.001 0.44

Thrombocytopenia 0(0.0) 2(0.1) 3(0.1) 0(0.0) 0(0.0) 0.94 0.88

Antithrombotic agents

Vitamin K antagonist 116(40.8) 1425(53.9) 1408(53.3) 129(44.9) 13(24.1) <0.001 0.32

Antiplatelet 81(28.5) 779(29.5) 897(34.0) 95(33.1) 22(40.7) <0.001 0.83

Any antithrombotic 175(61.6) 1965(74.3) 1990(75.4) 205(71.4) 30(55.6) <0.001 0.83

Other therapies

ACEI 36(12.7) 477(18.0) 549(20.8) 58(20.2) 9(16.7) 0.27 0.26

Beta-blocker 46(16.2) 602(22.8) 677(25.6) 70(24.4) 11(20.4) 0.10 0.93

Digoxin 34(12.0) 322(12.2) 373(14.1) 35(12.2) 5(9.3) 0.14 0.06

Diuretic 38(13.4) 438(16.6) 679(25.7) 96(33.4) 23(42.6) <0.001 <0.001

Antiarrhythmic agent 66(23.2) 739(28.0) 764(28.9) 82(28.6) 14(25.9) 0.74 0.53

Calcium channel blocker 8(2.8) 89(3.4) 112(4.2) 14(4.9) 4(7.4) 0.02 0.30

CHADS2

Low (score=0) 128(45.1) 788(29.8) 290(11.0) 3(1.0) 2(3.7) <0.001 <0.001

Intermediate (score=1) 64(22.5) 712(26.9) 661(25.0) 52(18.1) 3(5.6) <0.001 <0.001

High (score≥2) 92(32.4) 1144(43.3) 1690(64.0) 232(80.8) 49(90.7) <0.001 <0.001

CHA2DS2-VASc

Low(score=0) 85(29.9) 379(14.3) 48(1.8) 0(0.0) 1(1.9) <0.001 <0.001

Intermediate (score=1) 68(23.9) 514(19.4) 186(7.0) 4(1.4) 1(1.9) <0.001 <0.001

High (score≥2) 131(46.1) 1751(66.2) 2407(91.1) 283(98.6) 52(96.2) <0.001 <0.001

HAS-BLED

Low(score=0) 132(46.5) 796(30.1) 197(7.5) 6(2.1) 0(0.0) <0.001 <0.001

Moderate(score=1-2) 134(47.2) 1708(64.5) 2130(80.7) 173(60.3) 26(48.2) <0.001 <0.001

High(score≥3) 18(6.3) 142(5.4) 314(11.8) 108(37.6) 28(52.0) <0.001 <0.001

SD:standard deviation; AF:atrial fibrillation; ICD:implantable cardiac defibrillator; INR:international

normalised ratio; CHADS2(1 point each for heart failure, hypertension, age ≥75, and diabetes, and 2 points for

prior stroke or thromboembolism); CHA2DS2-VASc (1 point for heart failure, hypertension, diabetes, vascular

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23

disease, age 65-74, and female gender; 2 points for prior stroke or thromboembolism and age ≥75); HAS-BLED

(Hypertension, Abnormal renal and/or liver function, Stroke, Bleeding history or predisposition, Labile

International Normalized Ratio (INR), Elderly (> 65 years)

*Age adjustment was performed by including age as a covariate in a logistic regression model

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24

Table 2. Event rates (95% confidence interval) per 1000 person years in patients with atrial fibrillation by renal function

*p-value for 2-sided chi-squared test. TE: thromboembolism. VKA: Vitamin K antagonist. HAS-BLED (Hypertension, Abnormal renal and/or liver function, Stroke,

Bleeding history or predisposition, Labile International Normalized Ratio (INR), Elderly (> 65 years)

Estimated glomerular filtration rate (in ml/min/1.73 m2)

≥60

n=2930

30-59

n=2641

<30

n=341

P*

Events Event rate Events Event rate Events Event rate

Ischaemic Stroke

Total

No VKA

VKA

108

49

59

4.0 (3.3-4.8)

4.1(3.1-5.4)

3.8(2.9-4.9)

151

73

78

6.3 (5.4-7.4)

7.5 (5.9-9.4)

5.5 (4.4-6.9)

20

13

6

6.6 (4.0-10.2)

8.1(4.3-13.8)

4.2(1.6-9.2)

0.004

0.007

0.23

Relative risk (VKA vs No VKA) 0.92(0.63-1.36) 0.72(0.52-1.01) 0.50(0.19-1.36)

Ischaemic Stroke/TE

Total

No VKA

VKA

169

71

98

6.2 (5.3-7.2)

6.0(4.7-7.6)

6.4(5.2-7.8)

231

117

114

9.7 (8.5-11.0)

12.0 (9.9-14.4)

8.1 (6.7-9.7)

34

23

11

11.2(7.8-15.7)

14.3(9.1-21.4)

7.8(3.9-13.9)

<0.001

<0.001

0.17


Ischaemic Stroke/TE/Mortality Total

No VKA

VKA

341

176

165

12.5 (11.2-13.9)

11.9(10.2-13.8)

10.7(9.1-12.5)

518

287

231

21.7 (19.9-23.7)

29.4 (26.1-33.0)

16.4 (14.4-18.7)

107

61

36

35.3(28.9-42.7)

37.9(29.0-48.7)

25.4(17.8-35.1)

<0.001

<0.001

<0.001


Haemorrhagic stroke

Total

No VKA

VKA

35

10

23

1.19(0.83-1.66)

0.84(0.41-1.55)

1.49(0.95-2.24)

43

17

24

1.63(1.18-2.19)

1.74(1.02-2.79)

1.70(1.09-2.54)

3

3

0

0.88(0.18-2.57)

1.86(0.38-5.45)

-

0.28

0.15

0.28

Relative risk (VKA vs No VKA) 1.78(0.84-3.75) 0.98(0.52-1.83) -

Major bleeding

Total

No VKA

VKA

194

65

129

7.1 (6.2-8.2)

4.4(3.4-5.6)

8.4(7.0-10.0)

221

95

126

9.3 (8.1-10.6)

9.7 (7.9-11.9)

9.0 (7.5-10.7)

57

24

23

18.8(14.3-24.4)

14.9(9.6-22.2)

16.2(10.3-24.3)

<0.001

<0.001

0.03


All-cause mortality

Total

No VKA

VKA

225

130

95

8.3 (7.2-9.4)

8.8(7.3-10.4)

6.2(5.0-7.5)

373

210

163

15.7 (14.1-17.3)

21.5 (18.7-24.7)

11.6 (9.9-13.5)

90

58

32

29.7(23.9-36.5)

36.0(27.4-46.6)

22.5(15.4-31.8)

<0.001

<0.001

<0.001

Relative risk (VKA vs No VKA) 0.53(0.40-0.70). 0.48(0.38-0.60) 0.52(0.31-0.86)

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25

Table 3.

Renal Impairment and Risk of Ischaemic Stroke/Thromboembolism: Results from Cox Regression Analyses

Hazard Ratio (CI)

Univariate analysis

Renal impairment 1.05(0.76-1.46)

eGFR (categoric variable) 1.15(0.90-1.47)

Adjusted for sex and age



Female gender 1.16(0.84-1.61)

Age per 5-y increase 1.04(0.99-1.02)

Adjusted for CHADS2 risk factors



Heart failure 0.91(0.65-1.27)

Hypertension 1.22(0.88-1.68)

Age ≥ 75 y 1.25(0.77-2.02)

Diabetes mellitus 1.22(0.82-1.80)

Previous stroke/thromboembolism 0.88(0.62-1.26)

Adjusted for baseline characteristics*



*adjusted for Table 1 risk factors and including age as a continuous covariate, the result is only displayed for renal impairment.

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26

Table 4. Renal impairment and risk of Ischaemic Stroke/TE: results from Cox regression analyses excluding patients on vitamin K

antagonist at baseline

Hazard Ratio (CI)

Univariate analysis



Adjusted for sex and age



Female gender 1.15(0.91-1.45)

Age per 5-y increase 1.15(1.05-1.25)

Adjusted for CHADS2 risk factors



Heart failure 1.00(0.61-1.64)

Hypertension 1.37(0.83-2.27)

Age ≥ 75 y 1.84(1.01-3.33)

Diabetes mellitus 1.13(0.61-2.08)

Previous stroke/thromboembolism 1.99(1.09-3.63)

Adjusted for baseline characteristics



*adjusted for Table 1 risk factors and including age as a continuous covariate, the result is only displayed for renal impairment.

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27

FIGURE LEGENDS

Figure 1: Study population by stage of renal impairment

Figure 2: Event rates for stroke/thromboembolism, major bleeding and all-cause mortality by age and sex

Figure 3: All-cause mortality, stroke/thromboembolism and major bleeding by renal failure, oral anticoagulation and stage of renal impairment

Figure 4: Hazard ratios for stroke/thromboembolism, major bleeding and all-cause mortality

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8,962

Atrial fibrillation

284(4.8%)

eGFR

>90ml/min/1.73m2

2646 (44.8%)

eGFR

60-89 ml/min/1.73m2

2641 (44.7%)

eGFR

30-59ml/min/1.73m2

287(4.9%)

eGFR

15-29ml/min/1.73m2

54 (0.9%)

eGFR

<15ml/min/1.73m2

Excluded:

1,804 patients with valvular disease

1246 with missing values on VKA treatment or serum creatinine levels

Page 30 of 37


of 37


WEB ONLY APPENDIX

Extended Methods

Study population

The methods of the Loire Valley Atrial Fibrillation Project have been previously reported30-

31. At the Centre Hospitalier Régional et Universitaire in Tours (France), all patients

diagnosed with non-valvular AF (NVAF) or atrial flutter by the cardiology department

between 2000-2010 were identified, thus excluding patients with mitral stenosis, valve

replacement or other valvular pathology which might explain AF. The institution includes

four hospitals covering all medical and surgical specialties; the only public institution in an

area of around 4,000 km², serving approximately 400,000 inhabitants. Patients were followed

from the first record of NVAF after 1 January 2000 (i.e. index date) up to the latest data

collection at the time of study (December 2010). Treatment at discharge was obtained by

screening hospitalisation reports, and information on comorbidities was obtained from the

computerised coding system. Patients were excluded from the study if there was no available

data regarding the baseline serum creatinine level (Figure 1).

For each patient, the CHADS227

and CHA2DS2-VASc28

scores (which are the most commonly

used and validated risk stratification schemes for IS/TE in patients with AF) were calculated

following the first diagnosis of AF during hospital admission. The CHADS2 score was the

sum of points obtained after adding one point for congestive heart failure, hypertension, age

≥75, and diabetes, and two points for previous stroke or TE27

. The CHA2DS2-VASc score

was the sum of points after adding one point for congestive heart failure, hypertension,

diabetes, vascular disease (including history of coronary, cerebrovascular or peripheral

vascular disease), age 65-74, and female gender, and two points for previous stroke or TE and

age ≥7528

. According to the two risk scores, patients with a score of 0 on either schema were

considered as ‘low risk’, 1 as ‘intermediate risk’, and ≥2 as ‘high risk’ of stroke and TE.

The HAS-BLED (Hypertension, Abnormal renal and/or liver function, Stroke, Bleeding

history or predisposition, Labile International Normalized Ratio (INR), Elderly (> 65 years),

Drugs (antiplatelet drugs or NSAIDS)/alcohol excess concomitantly) score is a validated

scoring system for bleeding risk stratification in AF patients21

. For each patient, the HAS-

BLED score was also calculated as the sum of the points obtained after adding one point for

Page 34 of 37


the presence of each individual factor). For this analysis, patients with HAS-BLED score of 0

were deemed to have ‘low’ bleeding risk, those with HAS-BLED scores of 1-2 and ≥3 were

classified as “moderate” and ‘high’ bleeding risk respectively.

During follow-up, information on outcomes of TE, stroke (ischaemic or haemorrhagic),

major bleeding, and all-cause mortality were recorded by active surveillance of hospital

administrative data. Major bleeding was defined as bleeding with a reduction in the

haemoglobin level of at least 2g per litre, or with transfusion of at least 1 unit of blood, or

symptomatic bleeding in a critical area or organ (e.g., intracranial, intraspinal, intraocular,

retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome)

or bleeding that causes death. All bleeding data were identified with the diagnosis coded in a

subsequent hospitalization during follow-up – thus, we recorded all 'hospitalizations with a

bleed' as an additional criterion for major bleeding.

Assessment of renal function

Renal failure was defined as reported history of renal failure, or baseline serum creatinine

level of >133 µmol/L in men and >115 µmol/L in women32

. In order to convert serum

creatinine from µmol/L to mg/dL, the former was multiplied by a conversion factor of 88.4.

Current consensus guidelines state that prediction equations have greater consistency and

accuracy than serum creatinine in the assessment of GFR22-24, 33-35

. In addition, prediction

equations are equivalent or better than 24-hour urine creatinine clearance in all but one

study22-24, 36

. In adults, the most widely-used and validated method for estimating GFR from

serum creatinine level is the isotope dilution mass spectrometry (IDMS)-traceable

Modification of Diet in Renal Disease (MDRD) Study equation22-24

. The laboratories where

biochemical analysis of creatinine levels was conducted were calibrated to be IDMS-

traceable. The MDRD equation was preferred to the more recently validated “CKD-Epi”

equation37

because there were very few patients aged≥75 years in cohorts used to validate this

equation whereas the current study population was unrestricted by age.

eGFR = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American)

where eGFR is the estimated glomerular filtration rate in mL/min/1.73 m2, Scr is serum

creatinine level in mg/dL. The African population in the study population was <1% and

therefore no correction factor for ethnicity was required in the MDRD calculation of eGFR.

Page 35 of 37


Statistical analysis

The study population was stratified into five categories according to eGFR (in ml/min/1.73

m2), corresponding to the stages of CKD: ≥90, 60-89, 30-59, 15-29, and <15 (Figure 1)

22-24.

Since data regarding proteinuria was not available, stage of renal impairment could not be

defined. Baseline characteristics were determined separately for the five eGFR strata, and

differences were investigated using chi-squared test for categorical covariates and Kruskal-

Wallis test for continuous covariates. Age-adjustment was performed by including age as a

covariate in a logistic regression model.

Event rates of IS/TE, bleeding and all-cause mortality were calculated for all patients by

eGFR category, stratifying by presence or absence of VKA therapy. Since VKA therapy was

the only form of OAC used during the study period, the terms, “VKA” and “OAC” are used

interchangeably in the analyses. Due to low numbers of patients and outcomes in the

categories with eGFR≥90 and <15 ml/min/1.73m2, rates were calculated for categories with

eGFR≥60, 30-59 and <30 ml/min/1.73m2. Haemorrhagic strokes were excluded from

analyses of “stroke” or “stroke/TE”. Event rates were also calculated by age and sex

categories. In each eGFR category, Cox-proportional hazards analyses were performed to

calculate 1-year survival for IS/TE, bleeding and all-cause mortality. Bivariate analyses of

event rates in different subgroups were used to calculate hazard ratios associated with renal

impairment and eGFR category.

Cox proportional-hazard regression models were constructed to investigate whether renal

impairment and eGFR were independent predictors of IS/TE. The risk associated with renal

impairment and eGFR were estimated in a univariate analysis, as well as a sex- and age-

adjusted analysis, an analysis adjusted for the risk factors included in the CHADS2 score, and

a multivariate analysis adjusted for all baseline characteristics in Table 1. All analyses were

repeated by eGFR category, and by combined stratification by renal impairment and eGFR.

Further, to test whether the results were influenced by patients initiating treatment with VKA,

we performed additional analyses excluding patients at the initiation of such treatment.

Finally, the net clinical benefit (NCB) was calculated, as originally proposed by Singer and

colleagues38

using the formula:

Page 36 of 37


Net clinical benefit (NCB) = IS rate on no treatment- IS rate on anticoagulant)-1.5(ICH rate

on no treatment- ICH rate on anticoagulant

…. where IS=ischaemic stroke and ICH=intracerebral haemorrhage, which is the most

serious form of bleeding associated with OAC use. A modified formula with “haemorrhagic

stroke” instead of “ICH” was used to calculate NCB for the different eGFR categories. The

NCB is used by clinicians and researchers as a validated method of balancing risk of

ischaemic stroke against intracerebral haemorrhage.

A two-sided p-value <0.05 was considered statistically significant. All analyses were

performed with SPSS statistical software version 18.0 (IBM,USA).

Page 37 of 37


a prospective study of estimated glomerular filtration rate and outcomes in patients with atrial...

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