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eGFR = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American) ..... However, eGFR is probably the most important indicator of renal .... Archibald G, Bartlett W, Brown A, Christie B, Elliott A, Griffith K, Pound S, Rappaport ...
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A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: The Loire Valley Atrial Fibrillation Project

Amitava Banerjee Laurent Fauchier Patrick Vourc'h

MPH DPhil1 MD PhD PhD

4

3

[email protected] [email protected] [email protected]

3

Christian R. Andres

MD, PhD

[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; 4Service 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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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,

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, 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.

4

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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.

4

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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,

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. 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 widelyused 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)

5

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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