The Quandary of Oral Anticoagulation in Patients With Atrial Fibrillation and Chronic Kidney Disease




Compared to patients with normal renal function, the prevalence of atrial fibrillation (AF) in chronic kidney disease (CKD) is increased, as is consequently the stroke prevalence in these patients. This increased risk of stroke in patients with CKD is caused not only by the increased prevalence of AF, but also by associated co-morbidities, and inherent platelet and vascular dysfunction. Paradoxically, imbalance in the same factors also increases the bleeding risk, imposing a dilemma as to whether anticoagulation should be prescribed or deferred, particularly in patients with end-stage renal disease (ESRD), in whom the bleeding diathesis and thromboembolic predisposition are most recalcitrant. Unfortunately, it is in this vulnerable population, in whom therapeutic options are most limited, that evidence-based studies relating to stroke prophylaxis are scarce, discordant and based only on registry observations. Pending randomized controlled studies on this issue, we will review important epidemiologic data and major recent registry-based studies that the clinician has to weigh when making the best decision on the issue of the prophylactic use of warfarin in patients with CKD with AF, focusing on patients with end-stage renal disease.


In the current review, we will examine relevant epidemiologic data and considerations in an attempt to help the clinician make the best decision on the issue of the prophylactic use of anticoagulation in patients with chronic kidney disease (CKD) with atrial fibrillation (AF). We will focus the discussion on patients with end-stage renal disease (ESRD; dialysis-dependent and non–dialysis-dependent patients with glomerular filtration rate (GFR) ≤15 ml/min) and patients with severe CKD (with GFR 15 to 30 ml/min).


CKD and AF


The prevalence of AF in patients with CKD is 15% to 20% in various studies, and it increases with age, markedly exceeding that of the general population in all age groups. Indeed, 13% of US patients treated with hemodialysis (HD) aged 65 to 75 years; 19% of those aged 75 to 85 years; and 23% of those >85 years have a history of AF. In a large meta-analysis, the overall prevalence of AF in patients with ESRD treated with HD or peritoneal dialysis was 11.6% and the overall incidence was 2.7 of 100 patient-years. In a large survey comprising almost 2.5 million US outpatients with AF aged 65 years or above, CKD was an associated co-morbidity in 32% of the subjects (see http://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Chronic-Conditions/Downloads/2012Chartbook.pdf ).




CKD and thromboembolism


CKD is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, all of which confer an increased thromboembolic risk. Vascular calcification, arterial stiffness, and hypertension, which are all associated with CKD, appear to play an additional role in the increased risk for stroke. Indeed, multiple studies have confirmed CKD as an independent risk factor for stroke after adjustments for conventional risk factors. A recent large meta-analysis comprising 63 cohort studies and 20 randomized control studies found an inverse linear relation between GFR and stroke risk, with a risk of stroke increasing 7% (hazard ratio [HR] 1.07, CI 1.04 to 1.09) for every 10 ml/min/1.73 m 2 decrease in GFR.




CKD and thromboembolism


CKD is associated with low-grade inflammation, endothelial dysfunction, and platelet activation, all of which confer an increased thromboembolic risk. Vascular calcification, arterial stiffness, and hypertension, which are all associated with CKD, appear to play an additional role in the increased risk for stroke. Indeed, multiple studies have confirmed CKD as an independent risk factor for stroke after adjustments for conventional risk factors. A recent large meta-analysis comprising 63 cohort studies and 20 randomized control studies found an inverse linear relation between GFR and stroke risk, with a risk of stroke increasing 7% (hazard ratio [HR] 1.07, CI 1.04 to 1.09) for every 10 ml/min/1.73 m 2 decrease in GFR.




CKD and bleeding


The risk of bleeding in CKD is clearly increased as a result of thrombocytopathy, caused by uremic toxins that inhibit release of platelet factors including serotonin and thromboxane resulting in inhibition of their adhesion and aggregation ability, and impaired glycoprotein IIb to IIIa receptor activation and its binding to fibrinogen and von Willebrand factor. Enhanced production of nitric oxide and prostacyclin due to endothelial dysfunction also act to inhibit platelet adhesion and aggregation, respectively. Bleeding has been reported in 40% to 50% of patients with chronic renal failure or on HD. Clinically, there is an increased risk of gastrointestinal bleeding and intracerebral hemorrhage in patients with CKD.




“Net clinical benefit” of warfarin anticoagulation in AF and ESRD


The concept of “net clinical benefit” aims to balance the risks of ischemic stroke and bleeding on oral anticoagulation (OAC) therapy and has been facilitated by registry data. The latest 2012 focused update of the European Society of Cardiology guidelines for the management of AF advocates using the CHA 2 DS 2 -VASc score (congestive heart failure/left ventricular dysfunction, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled]—vascular disease, age 65 to 74 years, and gender category [women]) for determining thromboembolic risk in patients with AF, with a score threshold ≥2 for administering anticoagulation but makes no definitive recommendation for patients with ESRD. Of note, this score was derived from patients without renal failure and may not be valid in ESRD. The European Society of Cardiology guidelines also recommend a formal bleeding risk assessment for all patients with AF, and in patients with an HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio (INR) of prothrombin time, elderly [e.g., age greater than 65 years, frailty, and so forth], drugs/alcohol concomitantly), score ≥3, caution is appropriate, and efforts to correct potentially reversible risk factors for bleeding are warranted. This recommendation is all the more pertinent in most of the elderly patients with ESRD as they will have a high HAS-BLED score. The latest 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of AF state that “for patients with nonvalvular AF with a CHA 2 DS 2 -VASc score ≥2 and who have end-stage CKD (creatinine clearance [CrCl] <15 ml/min) or are on HD, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for OAC.” This recommendation in the AHA/ACC guidelines is based solely on a medium-sized prospective cohort study published in 2011 by Winkelmayer et al. The cohort consisted of 2,313 patients with HD aged >65 years with new AF who survived 30 days after hospital discharge. Comparing 237 warfarin users and 948 propensity-matched nonusers over 2,287 person-years of follow-up, the occurrence of ischemic stroke was similar (HR 0.92, 95% CI 0.61 to 1.37), whereas warfarin users experienced twice the risk of hemorrhagic stroke (HR 2.38, 95% CI 1.15 to 4.96). The risks of stroke, gastrointestinal hemorrhage, and mortality did not differ between groups. Analyses restricted to patients with CHADS 2 score ≥2 yielded similar findings. The recommendation accorded to warfarin use in these patients is surprising considering that the results of this particular study on which it was based do not indicate that warfarin-treated HD patients fared any better and considering additional large registry-based studies that were published in recent years looking at this issue which were not accounted for in the AHA/ACC AF guidelines. The study populations and number of patients in each of these studies are detailed in Tables 1 and 2 . Mortality, ischemic stroke risk, and the overall stroke risk (ischemic and hemorrhagic) with warfarin treatment in patients with ESRD are presented in Figures 1 to 3 for these studies where respective data were available.



Table 1

Recent large registry studies of net negative clinical outcome in patients with AF with ESRD treated with warfarin versus without warfarin





























Study Population Studied N Follow-up Period (yrs)
Shah (2014) Canadian patients on dialysis admitted with AF 1635 N/A
Winkelmayer (2011) US Medicare beneficiaries on dialysis with new AF 1185 Median 1.2
Wizeman (2010) Multi-national hemodialysis patients 3250 N/A
Chan (2009) Incident hemodialysis patients with AF 1671 Mean 1.6


Table 2

Recent large registry studies of net positive clinical outcome in patients with AF with ESRD treated with warfarin versus without warfarin





























Study Population Studied N Follow-up Period (yrs)
Bonde (2014) Danish national registries: patients on dialysis or kidney transplantees from 1997 to 2011 1728 Median 1.6
Carrero (2014) ESRD Swedish patients admitted with myocardial infarction during 2003-2010 478 N/A
Friberg (2015) Swedish health registries: all CKD levels including dialysis and kidney transplantees 13,435 patients with CKD, 833 on dialysis and 314 kidney transplantees Median 2.1
Olesen (2012) Danish national registries: patients on dialysis or kidney transplantees from 1997 to 2008. 901 N/A



Figure 1


HR for mortality according to warfarin use in patients on dialysis or renal replacement therapy (dialysis or kidney transplant). Further details on the study populations can be found in Tables 1 and 2 . Patients treated with renal replacement therapy (on dialysis or renal transplantees).



Figure 2


HR for ischemic stroke according to warfarin use in patients on dialysis or renal replacement therapy. Patients treated with renal replacement therapy (on dialysis or renal transplantees).



Figure 3


HR for all stroke (ischemic and hemorrhagic) according to warfarin use in patients on dialysis or renal replacement therapy. For patients aged 66 to 75 years. ¥ For patients aged >75 years. Patients treated with renal replacement therapy (on dialysis or renal transplantees).




Studies showing net clinical risk for warfarin anticoagulation in AF and ESRD


In a retrospective cohort study of 1,671 patients with ESRD and coexisting AF, warfarin use was associated with a statistically increased incidence of ischemic and hemorrhagic stroke. Warfarin users who received no INR monitoring in the first 90 days of dialysis had the highest risk for stroke compared with nonusers. Warfarin use did not associate with statistically significant increases in all-cause mortality or hospitalization. Bleeding risk and INR control were not determined.


Using data from the international Dialysis Outcomes and Practice Patterns Study, Wizemann et al also reported that in patients with AF anticoagulation with warfarin treated with HD were associated with an increased incidence of stroke especially in patients aged >75 years. The limitations of this study included data collection exclusively through questionnaires, potentially inducing inaccuracy in AF detection; combining both ischemic and hemorrhagic stroke for stroke outcome; and lack of bleeding risk assessment.


Another negative retrospective cohort study was recently published by a Canadian group. They showed that in 1,626 patients treated with dialysis with AF, warfarin use, in comparison with no warfarin use, did not reduce the risk for stroke but was associated with a 44% higher adjusted HR for a bleeding event, whereas warfarin use in nondialysis patients with AF was associated with a 13% lower adjusted HR for stroke and only a 19% higher HR for bleeding event. Propensity score–adjusted analyses yielded similar results. INR levels were not available in this study.

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Nov 27, 2016 | Posted by in CARDIOLOGY | Comments Off on The Quandary of Oral Anticoagulation in Patients With Atrial Fibrillation and Chronic Kidney Disease

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