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Corresponding author: Dr Robert G. Hart, Division of Neurology, Department of Medicine, McMaster University/Population Health Research Institute, Hamilton General Hospital/DBCVSRI C4-105, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. Tel.: +1-905-521-2100 ×41152; fax: +1-905-577-1427.
Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Working Group Members Evaluation and management of chronic kidney disease: synopsis of the KDIGO 2012 clinical practice guidelines.
assessed 7 previously published risk prediction models for stroke and major bleeding in patients with AF and found them to be poorly predictive in patients with AF and CKD.
Kidney Disease Outcomes Quality Initiative (KDOQI) criteria.1 Renal function is sometimes expressed as estimated creatinine clearance using the Cockcroft-Gault equation that usually exceeds the estimated GFR, particularly at an estimated GFR about 30 mL/min/1.73m2. Because many clinical laboratories automatically provide an estimated GFR that accompanies measurement of serum creatinine levels, use of the antiquated estimated creatinine clearance should be abandoned.2 The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines additionally incorporate albuminuria into classification of renal function.3 Albuminuria is an independent predictor of major bleeding.4
Renal function is sometimes expressed as estimated creatinine clearance using the Cockcroft-Gault equation that usually exceeds the estimated GFR, particularly at an estimated GFR about 30 mL/min/1.73m2. Because many clinical laboratories automatically provide an estimated GFR that accompanies measurement of serum creatinine levels, use of the antiquated estimated creatinine clearance should be abandoned.
Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Working Group Members Evaluation and management of chronic kidney disease: synopsis of the KDIGO 2012 clinical practice guidelines.
This retrospective (2002-2013) longitudinal cohort study was based on Alberta Health administrative databases and included 55,451 patients with incident nonvalvular AF who were not treated with anticoagulants and who were followed for a mean of 2.6 years.
Patient groups that were not included because of specific inclusion criteria warrant mention: 24,415 patients with AF who were prescribed anticoagulation therapy were not included nor were 25,567 patients with AF in whom kidney function was not measured within 3 months of diagnosis. Patients with AF receiving renal replacement therapy or those who had undergone previous renal transplantation were also excluded. These stipulations contributed to a relatively young AF study cohort (mean age, 66 years, which is 5-10 years younger than typical AF cohorts), with 11% having a history of previous bleeding. Also of note, thromboembolic outcomes included transient ischemic attacks (35%), and the definition of major hemorrhage was “any bleed requiring emergency department visit or hospitalization, intracranial hemorrhage, or gastrointestinal bleeding” (different from and not comparable to the criteria used in recent large randomized trials). CKD defined by reduced (< 60 mL/min/1.73m2) estimated glomerular filtration rate (eGFR) was present in 24% (and in 31% if additionally considering albuminuria). The observed stroke rate during follow-up of 3.2% per year is relatively high for a cohort with a median CHADS2 (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack) score of 1 and a mean CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age [≥ 75 years], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 years], Sex [Female] score) of 3 (expected stroke rate of about 2%/y).
The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy.
Both the rates of stroke and of major bleeding increased progressively in parallel with the severity of CKD.
Sophisticated statistical analyses were undertaken to assess the predictive value of 7 widely used risk-stratification schemes (4 for prediction of thromboembolism and 3 for major bleeding) in the subgroup of patients with AF and CKD.
All schemes performed better in patients with AF without CKD, with poor discrimination in patients with CKD in proportion to CKD severity. The investigators concluded that these risk stratification schemes were inadequate for clinical decision-making in patients with AF and CKD.
Furthermore, extracranial bleeding during anticoagulation is more than just a nuisance; it initiates a series of “consecutively falling dominos” that result in increased mortality.
Interestingly, the clinical consequences of bleeding during antithrombotic therapies have sometimes been underestimated by regulatory agencies but not by practitioners, who tend to be excessively adverse to bleeding risk when considering antithrombotic drugs for stroke prophylaxis.
In our view, anticoagulation for stroke prevention should be routinely considered for all patients with AF who are ≥ 65 years of age with moderate CKD (ie, eGFR 30-59 mL/min). The recently introduced direct-acting oral anticoagulants (DOACs) are preferred over warfarin for prevention of stroke in patients with AF, including those with moderate CKD.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials.
Based on currently available data, we favor apixaban as the anticoagulant of choice for patients with AF and CKD because it is less dependent on renal clearance than are other DOACs.
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time. Insights from the ARISTOTLE randomized clinical trial.
The benefits vs risks of anticoagulation for stroke prevention in patients with AF with a eGFR < 30 mL/min/1.73m2 or with end-stage CKD are less clear and are controversial.
Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.
Patients with AF undergoing hemodialysis are at substantially increased risk both of ischemic stroke and of serious bleeding (including intracranial bleeding). Both the US Food and Drug Administration (FDA) and the European Medicines Agency have approved the use of apixaban and rivaroxaban in patients with an eGFR 15-30 mL/min; the FDA also approved dabigatran for these patients. In 2014, the FDA extended the approval of apixaban to patients with AF undergoing hemodialysis based on limited pharmacokinetic data,
The value of warfarin anticoagulation is unclear even for secondary stroke prevention (ie, the highest risk for recurrent stroke) in patients with AF undergoing hemodialysis based on the most recent meta-analysis of observational studies,
and the net clinical benefit of anticoagulation for primary prevention of stroke remains dubious for patients undergoing hemodialysis because of excessive bleeding risk.
We lament the absence of randomized trials to address this important issue. CKD clinical investigators seem addicted to large observational “big data” studies with contradictory results that are inevitably prone to confounding.
In the absence of reliable risk prediction schemes for stroke or bleeding in these patients, we favour anticoagulation with a DOAC for patients with AF who are ≥ 65 years old and have moderate or severe CKD (Table 1) (we also recommend the use of the Canadian Cardiovascular Society 2016 Guideline algorithm for younger patients).
for the CCS Atrial Fibrillation Guidelines Committee 2016 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.
Optimal antithrombotic treatment to prevent stroke in patients with AF and end-stage CKD is much less clear. At present, we restrict anticoagulation to those at highest risk (previous cardioembolic stroke) and treat with carefully monitored warfarin, pending more data about DOAC safety in these patients.
Disclosures
Dr Hart receives research support and research stipends from Bayer Healthcare and Bristol Myers-Squibb. Dr Ingram reports no conflicts of interest. Dr Eikelboom has received honoraria and research support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichi-Sankyo, Janssen, and Pfizer.
References
Hart R.G.
Eikelboom J.W.
Brimble K.S.
McMurty M.S.
Ingram A.J.
Stroke prevention in atrial fibrillation patients with chronic kidney disease.
The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials.
Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time. Insights from the ARISTOTLE randomized clinical trial.
Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.
Comparative effectiveness studies are common in patients with nonvalvular atrial fibrillation (NVAF) and chronic kidney disease (CKD), but the accuracy of current thromboembolic (n = 4) and bleeding (n = 3) prediction scores used for risk adjustment are uncertain in these patients because previous studies have included few CKD patients.
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