The importance of preserving kidney function in atrial fibrillation
Why does kidney function matter in atrial fibrillation?
Having better kidney function is associated with improved outcomes in patients with atrial fibrillation (AF). Indeed, kidney impairment is associated with an increased risk of stroke and embolic events, bleeding and death in patients with non-valvular AF (NVAF),1-3 emphasizing the importance of preserving kidney function to avoid adverse outcomes. Further bringing this point into focus is evidence that patients with AF have an increased risk of kidney impairment, and conversely, that patients with kidney impairment have an increased risk of AF.4
The risk of kidney dysfunction in patients with AF, and the risk of AF in patients with kidney impairment4
Another factor that influences kidney function that becomes relevant when treating patients with AF is the use of anticoagulants. In particular, excessive anticoagulation with vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs) may accelerate progression of chronic kidney disease (CKD) by inducing anticoagulant-related nephropathy (ARN), defined as acute kidney injury (AKI) without obvious aetiology in the presence of an international normalized ratio of >3.0.5,6 ARN has been associated with increased patient mortality.5
Diabetes poses an additional threat to the kidney in patients with AF
A patient with AF who also has diabetes presents a specific challenge to kidney function. Through the effects of diabetic kidney disease, this patient becomes at risk of CKD.7 With diabetes being a key risk factor for AF,8 and with both diabetes and AF being associated with kidney impairment,4,7 a patient with AF and diabetes may be at risk of rapidly worsening kidney function that may soon lead to kidney impairment and its deleterious effects on outcomes. Indeed, the patient with AF and diabetes has an elevated risk of thromboembolism and death that worsens over time.9
What can we do to preserve kidney function in patients with AF?
The risk posed by co-morbid diabetes and kidney impairment in patients with AF emphasizes the importance of employing opportunities that preserve kidney function and reduce the risk of stroke and systemic embolic events. With this in mind, the 2019 update to the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines note that NOACs, in particular rivaroxaban and dabigatran, may be associated with lower risks of adverse renal outcomes than warfarin in patients with AF.10
What evidence supports the kidney-preserving effects of NOACs?
Data supporting the effects of NOACs on preserving kidney function in patients with AF have recently been published. The real-world studies RELOADED, CALLIPER and a US MarketScan claims database analysis, revealed how the choice of anticoagulant may influence renal outcomes in patients with AF.11-16
RELOADED
RELOADED was an observational, retrospective study of German claims data in patients with NVAF and kidney disease initiating either rivaroxaban, apixaban, edoxaban or phenprocoumon, for the first time. The study showed that rivaroxaban and apixaban were associated with a reduced risk of progression to end-stage renal disease (ESRD) or dialysis compared with the VKA, phenprocoumon.11
Risk of progression to ESRD or dialysis with rivaroxaban and apixaban compared with phenprocoumon among patients with NVAF and kidney disease in RELOADED11
For the outcome of ESRD alone, both rivaroxaban and apixaban reduced the risk of an event by 73% and 57%, respectively, compared with phenprocoumon.12 Furthermore, there was a trend towards a reduced risk of AKI with each of the NOACs compared with phenprocoumon – this effect being most pronounced for rivaroxaban.12 As expected, the efficacy of rivaroxaban and apixaban was comparable to phenprocoumon, while both NOACs were associated with an improved safety profile.12
Risk of ESRD and AKI with NOACs compared with phenprocoumon among patients with NVAF and kidney disease in RELOADED1212
Similarly, in patients with AF also presenting with diabetes, those receiving a NOAC experienced better kidney preservation than those who received a VKA. Analysis of data from a German claims database demonstrated that patients with AF and co-morbid diabetes taking rivaroxaban or apixaban experienced 68% and 40% significantly reduced risks of ESRD, respectively, compared with those taking phenprocoumon.13 Furthermore, rivaroxaban reduced the risk of patients developing AKI by 28% compared with phenprocoumon.13
CALLIPER
CALLIPER was a study that analysed claims data in US patients with NVAF and CKD stage 3 or 4 initiating either rivaroxaban or warfarin. Results showed rivaroxaban reduced the risk of progression to CKD stage 5, kidney failure or dialysis by 47% compared with warfarin. In NVAF patients with CKD stage 3 or 4 also presenting with type 2 diabetes, there was a 50% reduction in risk of the composite renal outcome with rivaroxaban compared with warfarin.14
Risk of progression to CKD stage 5, kidney failure or dialysis with rivaroxaban compared with warfarin in CALLIPER14
US MarketScan claims database analysis This analysis was based on claims data derived from patients with NVAF newly initiated on rivaroxaban or warfarin. Results showed that rivaroxaban reduced the risk of AKI by 19% and CKD stage 5 or dialysis by 18% compared with warfarin.15
Risk of AKI and CKD stage 5 or dialysis with rivaroxaban compared with warfarin among patients with NVAF in a US MarketScan claims database analysis15
Similarly, when assessing US MarketScan claims data for patients with NVAF and co-morbid diabetes, patients taking rivaroxaban experienced a lower risk of undesirable renal outcomes compared with patients taking warfarin. Patients taking rivaroxaban also experienced lower risks of AKI (hazard ratio [HR]=0.83; 95% confidence interval [CI] 0.74−0.92) and development of stage 5 CKD or need for haemodialysis (HR=0.82; 95% CI 0.70−0.96) compared to those taking warfarin.16
Risk of AKI and CKD stage 5 or need for haemodialysis with rivaroxaban compared with warfarin in patients with NVAF and diabetes16
Summary
Preservation of kidney function is an important consideration in AF; kidney impairment increases the patient’s risk of stroke and embolic events, bleeding and death.1-3 An increased risk of thromboembolism and death is also evident for patients with AF presenting with diabetes, which can cause CKD.7,9 Therefore, it is prudent to consider treatment strategies that preserve kidney function in AF. Indeed, ACC/AHA/HRS guidelines suggest that NOACs may have a role in this regard.10 Real-world studies support this, with data showing improved renal outcomes with rivaroxaban and apixaban compared with VKAs in patients with AF, as well as patients with AF and diabetes.11-16
Identifying ARN in practice
There are several clinical findings that may suggest the presence of ARN. If patients meet any of the criteria to suspect ARN, a kidney biopsy should be performed to confirm a diagnosis17
Criteria for clinical suspicion of ARN17
References
- Boriani G., Laroche C., Diemberger I. et al. Glomerular filtration rate in patients with atrial fibrillation and 1-year outcomes. Sci Rep. 2016;6:30271. Return to content
- Fanikos J., Burnett A.E., Mahan C.E. et al. Renal function considerations for stroke prevention in atrial fibrillation. Am J Med. 2017;130(9):1015–23. Return to content
- Kulkarni N, Gukathasan N, Sartori S, Baber U. Chronic kidney disease and atrial fibrillation: a contemporary overview. J Atr Fibrillation 2012;5:448. Return to content
- Watanabe H, Watanabe T, Sasaki S et al. Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. Am Heart J 2009;158:629–636. Return to content
- Wheeler D, Giugliano R, Rangaswami J. Anticoagulation-related nephropathy. J Thromb Haemost 2016;14:461–467. Return to content
- Brodsky SV, Nadasdy T, Rovin BH et al. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate. Kidney Int 2011;80:181-189. Return to content
- Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017;12:2032–2045. Return to content
- Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014;114:1453–1468. Return to content
- Overvad TF, Skjoth F, Lip GY et al. Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study. Stroke 2015;46:2168–2174. Return to content
- January CT, Wann LS, Calkins H et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation 2019;140:e125–e151. Return to content
- Bonnemeier H, Kreutz R, Enders D et al. Renal function worsening in Factor-Xa inhibitors vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - insights from the RELOADED study. European Society of Cardiology Congress. Paris, France, 31 August–5 September 2019, Poster P4749. Return to content
- Bonnemeier H, Kreutz R, Kloss S et al. Comparative safety and effectiveness of non-vitamin-K oral anticoagulants vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - results from the RELOADED study. 5th European Stroke Organisation Conference. Milan, Italy, 22–24 May 2019, Abstract AS25-066. Available at: https://journals.sagepub.com/toc/esoa/4/1_suppl [accessed 20 November 2019]. Bonnemeier H, Kreutz R, Kloss S et al. Comparative safety and effectiveness of non-vitamin-K oral anticoagulants vs phenprocoumon in patients with non-valvular atrial fibrillation and renal disease - results from the RELOADED study. 5th European Stroke Organisation Conference. Milan, Italy, 22–24 May 2019, Abstract AS25-066. Available at: https://journals.sagepub.com/toc/esoa/4/1_suppl [accessed 20 November 2019]. Return to content
- Bonnemeier H, Kreutz R, Kloss S et al. Comparative safety and effectiveness of non-vitamin-K oral anticoagulants vs phenprocoumon in patients with non-valvular atrial fibrillation and diabetes - results from the RELOADED study. 5th European Stroke Organisation Conference. Milan, Italy, 22–24 May 2019, AS25-069. Available at: https://journals.sagepub.com/toc/esoa/4/1_suppl [accessed 20 November 2019]. Bonnemeier H, Kreutz R, Kloss S et al. Comparative safety and effectiveness of non-vitamin-K oral anticoagulants vs phenprocoumon in patients with non-valvular atrial fibrillation and diabetes - results from the RELOADED study. 5th European Stroke Organisation Conference. Milan, Italy, 22–24 May 2019, AS25-069. Available at: https://journals.sagepub.com/toc/esoa/4/1_suppl [accessed 20 November 2019]. Return to content
- Vaitsiakhovich T, Coleman CI, Kleinjung F et al. Worsening of renal function in atrial fibrillation patients with stage 3 or 4 chronic kidney disease treated with warfarin or rivaroxaban - evidence from the real-world CALLIPER study in the US claims. European Society of Cardiology Congress. Paris, France, 31 August–5 September 2019, Poster P4746. Return to content
- Coleman CI, Kreutz R, Sood N et al. Rivaroxaban's impact on renal decline in patients with nonvalvular atrial fibrillation: A US MarketScan claims database analysis. Clin Appl Thromb Hemost 2019;25:1076029619868535. Return to content
- Hernandez AV, Bradley G, Khan M et al. Rivaroxaban versus warfarin and renal outcomes in non-valvular atrial fibrillation patients with diabetes. Eur Heart J Qual Care Clin Outcomes 2019: doi:10.1093/ehjqcco/qcz047. Return to content
- Glassock RJ. Anticoagulant-related nephropathy: it's the real McCoy. Clin J Am Soc Nephrol 2019;14:935–937. Return to content
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Time for a change? Switching anticoagulants in patients with AF or VTE
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