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Challenging Anticoagulation in Advanced Renal Failure

      SEE RELATED ARTICLE, p. 1335
      Chronic kidney disease patients with atrial fibrillation experience high rates of atrial fibrillation-related complications. Nevertheless, in severe chronic kidney disease, the evidence of oral anticoagulation to prevent thromboembolic events and to reduce mortality remains unclear. Indeed, the pivotal trials comparing non-vitamin K antagonist oral anticoagulants (NOACs) to vitamin-K antagonists had severe kidney dysfunction as a general exclusion criterion.

      Zhang L, Steckman DA, Adelstein EC, et al. Oral Anticoagulation for atrial fibrillation thromboembolism prophylaxis in the chronic kidney disease population: the state of the art in 2019. Cardiovasc Drugs Ther. doi: https://doi.org/10.1007/s10557-019-06885-x, accessed July 27, 2019 [epub ahead of print]

      Patients with advanced chronic kidney disease generally display broad polymorbidity (e.g., hypertension, heart disease, diabetes mellitus, and episodes of acute on chronic kidney failure) and polypharmacy, which makes it difficult to keep anticoagulation in a constant therapeutic range. Beyond and above these aspects, chronic kidney disease represents a major risk factor for cardiovascular diseases by and large (e.g., through premature aging of blood vessels as expressed by accelerated vascular calcification).
      • Kooman J.P.
      • Dekker M.J.
      • Usvyat L.A.
      • et al.
      Inflammation and premature aging in advanced chronic kidney disease.
      • Go A.S.
      • Chertow G.M.
      • Fan D.
      • McCulloch C.E.
      • Hsu C.Y.
      Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
      This makes patients with advanced chronic kidney disease a high-risk group for a wide range of complications, including thromboembolic events and bleeding.
      Thus, the coexisting, predominating wide range of pathologies may make it difficult to detect benefits from oral anticoagulants. Moreover, based on the uremia-related bleeding tendency, anticoagulants are recognized to cause increased bleeding episodes, and each individual anticoagulant has unique pharmacologic properties of which treating physicians need to be knowledgeable about.
      • Jain N.
      • Reilly R.F.
      Clinical pharmacology of oral anticoagulants in patients with kidney disease [epub ahead of print].
      Of note is the recently described entity of warfarin nephropathy that can lead by itself to kidney failure.
      • Brodsky S.
      • Eikelboom J.
      • Hebert L.A.
      Anticoagulant-related nephropathy.
      In this issue of The American Journal of Medicine, Chang and colleagues
      • Chang S.H.
      • Wu C.V.
      • Yeh Y.H.
      • et al.
      Efficacy and safety of oral anticoagulants in patients with atrial fibrillation and stages 4 or 5 chronic kidney disease.
      analyzed a single-center dataset of 3771 patients with atrial fibrillation and an estimated glomerular filtration rate of <30. Among those patients, 2971 were non-anticoagulated, 280 were treated with a NOAC, and 520 received warfarin. The mean follow-up was 3.2 years. After adjusting for gender, age, comorbidities, and co-medications, the warfarin group had a significantlyhigher risk of ischemic stroke or systemic embolism (adjusted hazard ratio [aHR] 3.1, 95% confidence interval [CI], 2.1-4.6) than the non-anticoagulated group. The NOAC group had a similar risk of ischemic stroke or systemic embolism (aHR 1.1; 95% CI, 0.3-3.4) to that of the non-anticoagulated group. Both the warfarin and the NOAC groups had a significantly higher major bleeding risk than the non-coagulated group (aHR 2.8 [95% CI, 2.0-3.8] for warfarin; aHR 3.1 [95% CI, 1.9-5.2] for NOAC). In their conclusion, the authors challenge the conventional use of any anticoagulant in this population of advanced chronic kidney disease.
      In considering the relevance of these data, it is a strength that this is a “real-world” dataset retrieved from a single center. However, although the sample size is large, the representation of NOACs patients (n=280) is rather modest. Importantly, the authors have investigated a particularly high-risk chronic kidney disease patient group with atrial fibrillation, namely older patients with a mean age of 78 years and advanced chronic kidney disease stages 4-5, but a relatively short mean follow-up of just over 3 years. Among the investigated cohorts, a large patient proportion was treated with (additional) platelet inhibitors, underscoring the potential polymorbidity of the investigated subjects. Other shortcomings of such a retrospective cohort study include duration and type of kidney disease and degree of albuminuria which are not stated. This is important since not all chronic kidney disease harbors an equal risk for thrombotic events; e.g., the nephrotic syndrome per se reflects a procoagulant state, especially in the context of membranous nephropathy.
      • Glassock R.J.
      Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum.
      Thus, one can assume that—to some extent—such patients may be overrepresented in the two study groups.
      Furthermore, the quality of anticoagulation (e.g., international normalized ratio range for warfarin) remains unknown. In this respect, the estimated glomerular filtration rate of patients in the present study was determined using the Modification of Diet in Renal Disease Study formula. However, as stated previously in this journal, the major pivotal clinical trials of NOACs against vitamin-K antagonists were based on creatinine clearance for patient inclusion with dose adjustments performed according to creatinine clearance.
      • Fernandez-Prado R.
      • Castillo-Rodriguez E.
      • Velez-Arribas F.J.
      • Gracia-Iguacel C.
      • Ortiz A.
      Creatinine clearance is not equal to glomerular filtration rate and cockcroft-gault equation is not equal to CKD-EPI collaboration equation.
      Furthermore, the severity (patient sequelae) of ischemic and hemorrhagic events were not reported. Finally, this dataset consists exclusively of Asian patients; therefore, any worldwide arbitration seems premature.
      The present study makes a significant contribution to the controversial field of oral anticoagulation in chronic kidney disease patients and advises against an unselected anticoagulant treatment of elderly chronic kidney disease stages 4-5 patients with atrial fibrillation to prevent thromboembolic events. Physicians are again left with an individualized approach to these patients weighing carefully in the inherent benefits and risks of oral anticoagulation.

      References

      1. Zhang L, Steckman DA, Adelstein EC, et al. Oral Anticoagulation for atrial fibrillation thromboembolism prophylaxis in the chronic kidney disease population: the state of the art in 2019. Cardiovasc Drugs Ther. doi: https://doi.org/10.1007/s10557-019-06885-x, accessed July 27, 2019 [epub ahead of print]

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        • Dekker M.J.
        • Usvyat L.A.
        • et al.
        Inflammation and premature aging in advanced chronic kidney disease.
        Am J Physiol Ren Physiol. 2017; 313: F938-F950
        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
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        • Reilly R.F.
        Clinical pharmacology of oral anticoagulants in patients with kidney disease [epub ahead of print].
        Clin J Am Soc Nephrol. 2018; https://doi.org/10.2215/CJN.02170218
        Date accessed: July 27, 2019
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        • Eikelboom J.
        • Hebert L.A.
        Anticoagulant-related nephropathy.
        J Am Soc Nephrol. 2018; 29: 2787-2793
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        • Wu C.V.
        • Yeh Y.H.
        • et al.
        Efficacy and safety of oral anticoagulants in patients with atrial fibrillation and stages 4 or 5 chronic kidney disease.
        Am J Med. 2019; https://doi.org/10.1016/j.amjmed.2019.06.006
        • Glassock R.J.
        Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum.
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        • Castillo-Rodriguez E.
        • Velez-Arribas F.J.
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        Creatinine clearance is not equal to glomerular filtration rate and cockcroft-gault equation is not equal to CKD-EPI collaboration equation.
        Am J Med. 2016; 129: 1259-1263