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American Journal of Kidney Diseases

Is Warfarin Being Relegated to the Pharmaceutical Dustbin?

  • Ziv Harel
    Correspondence
    Address for Correspondence: Ziv Harel, MD, MSc, 61 Queen St, 7th floor, Toronto, ON M5C 2T2, Canada.
    Affiliations
    Division of Nephrology, Department of Medicine, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
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  • Manish M. Sood
    Affiliations
    Department of Medicine, The Ottawa Hospital, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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      Related Article, p. 180
      Since the introduction of the direct oral anticoagulants (DOACs) into clinical practice, they have been increasingly prescribed for the management of atrial fibrillation. Among the DOACs, apixaban has been used most frequently in the chronic kidney disease (CKD) population primarily owing to its favorable pharmacokinetic profile. Importantly, a steady stream of evidence consistently demonstrates apixaban’s superior efficacy for stroke prevention and improved safety (ie, a decreased risk of bleeding) among individuals with atrial fibrillation and CKD, as compared to vitamin K antagonists (VKAs).
      • Ha J.T.
      • Neuen B.L.
      • Cheng L.P.
      • et al.
      Benefits and harms of oral anticoagulant therapy in chronic kidney disease: a systematic review and meta-analysis.
      • Hohnloser S.H.
      • Hijazi Z.
      • Thomas L.
      • et al.
      Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial.
      • Harel Z.
      • Sholzberg M.
      • Shah P.S.
      • et al.
      Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD.
      Of interest, DOACs and VKAs also demonstrate differential effects on the kidney. It is well established that VKAs have erratic pharmacokinetic profiles, and hence their use may expose individuals to kidney injury mediated through a number of mechanisms, including anticoagulant-related nephropathy resulting from over-anticoagulation, as well as hypotension from systemic bleeding.
      • Brodsky S.
      • Eikelboom J.
      • Hebert L.A.
      Anticoagulant-related nephropathy.
      VKAs may also promote vascular calcification owing to their inhibition of matrix Gla protein.
      • Cozzolino M.
      • Fusaro M.
      • Ciceri P.
      • Gasperoni L.
      • Cianciolo G.
      The role of vitamin K in vascular calcification.
      Although the clinical significance of this on kidney function has not been elucidated, one may hypothesize that calcification of the kidney vasculature could lead to persistent ischemic injury. Taken together, these events may contribute to a loss of kidney function, especially among users with pre-existing CKD, who are particularly susceptible owing to their limited kidney reserve. In contrast, the limited drug interactions and favorable pharmacokinetic profile of apixaban, combined with its newly discovered anti-inflammatory properties, may mitigate the risk of kidney injury.
      • Nakase T.
      • Moroi J.
      • Ishikawa T.
      Anti-inflammatory and antiplatelet effects of non-vitamin K antagonist oral anticoagulants in acute phase of ischemic stroke patients.
      In this issue of AJKD, Wetmore et al
      • Wetmore J.B.
      • Yan H.
      • Herzog C.A.
      • Weinhandl E.
      • Reyes J.L.
      • Roetker N.S.
      CKD progression in Medicare beneficiaries with nonvalvular atrial fibrillation treated with apixaban versus warfarin.
      examined the associations of the use of apixaban versus warfarin with (1) time to kidney failure onset and (2) time to CKD stage progression, among Medicare recipients with stage 3, 4, or 5 CKD and new-onset atrial fibrillation between 2014 and 2017. CKD progression was identified based on 2 or more diagnoses for a more advanced CKD stage using International Classification of Diseases (ICD) codes that had to be separated by at least 30 days. A total of 12,816 Medicare recipients met all inclusion criteria, with 6,443 (50.3%) in the apixaban group and 6,373 (49.7%) in the warfarin group. The majority of included individuals had stage 3 CKD (approximately 85%). Marginal structural models with inverse probability treatment weighting were used to balance the baseline characteristics between the 2 groups. A further step of estimating the inverse probability of censor weighting was performed that accounted for informative censoring (ie, competing risks). An intention-to-treat analysis with a median follow-up of roughly 2 years demonstrated no difference in the rate of kidney failure between the apixaban and warfarin groups (2.1% per 100 patient-years for each; adjusted hazard ratio [AHR], 0.98 [95% CI, 0.79-1.22]). However, apixaban users had a 10% lower risk of CKD progression than warfarin users (AaHR, 0.90 [95% CI, 0.82-0.99]). The lower risk of CKD progression was only found among individuals with stage 3 CKD, rather than across all strata of CKD stages [AHRs of 0.9 [95% CI, 0.81-1.00; P= 0.04] for stage 3 CKD and 0.95 [95% CI, 0.74-1.22; P= 0.7] for stage 4-5 CKD]. In a subgroup analysis, there was no difference in the risk of kidney failure between apixaban and warfarin.
      Previous studies had attempted to disentangle the relationship between apixaban, VKAs, and the progression of kidney disease. For example, a post hoc analysis of the ARTISTOLE trial did not find a significant difference in the decline in kidney function over 1 year (defined as a decrease in estimated glomerular filtration rate [eGFR] by greater than 20%) among warfarin versus apixaban users in the entire cohort.
      • Hijazi Z.
      • Hohnloser S.H.
      • Andersson U.
      • et al.
      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.
      However, the authors did not report data for individuals with CKD randomized to each therapy who had a decline in kidney function. Similarly, a large observational trial of almost 10,000 patients with atrial fibrillation prescribed an oral anticoagulant also failed to demonstrate a significant difference between individuals with CKD (GFR < 60 mL/min) receiving apixaban compared to warfarin and kidney disease progression (defined as a 30% decline in GFR, doubling of serum creatinine, or progression to kidney failure).
      • Yao X.
      • Tangri N.
      • Gersh B.J.
      • et al.
      Renal outcomes in anticoagulated patients with atrial fibrillation.
      Interestingly, CKD progression was significantly lower overall with DOAC users compared to warfarin, driven by beneficial effects with dabigatran and rivaroxaban. This suggests a few possibilities, including that the kidney benefits are specific to DOAC type or the sample of apixaban users was too small and therefore was inadequately powered to detect a difference between apixaban and warfarin users.
      The study by Wetmore et al expands upon these previous works, as it included a large number of apixaban users and focuses on a high-risk group of individuals (those with underlying CKD). However, the results presented herein should be interpreted within the confines of some important considerations.
      In keeping with the aforementioned 2 studies, Wetmore’s study also did not define CKD progression according to the KDIGO criteria—a decline in GFR category accompanied by a 25% or greater drop in eGFR from baseline, or a sustained decline in eGFR by more than 5 mL/min/1.73 m2 per year.
      Kidney Disease Working Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      This may have led to misclassifying some individuals as having CKD progression for a number of reasons. First, the study’s use of ICD codes to define CKD may have excellent specificity, but ICD codes lack granularity. As a result, individuals at the extremes of a given CKD stage (ie, 59 vs 31 mL/min/1.73 m2) would be treated equally in terms of their risk for CKD progression when that may have not been the case. Second, whereas it is well established that CKD progression typically occurs over a long period of time and in a nonlinear manner, the study by Wetmore et al had a fairly short duration between consecutive ICD codes (at least 30 days) and also lacked any measurement of GFR. Hence, it is possible that patients that developed the outcome of CKD progression in this study may have had trivial changes in their GFR (ie, from 31 to 29 mL/min/1.73 m2) and/or were recovering from an episode of acute kidney injury and/or were prescribed a new medication (eg, inhibitors of angiotensin-converting enzyme or sodium/glucose cotransporter 2) that may have led to hemodynamic changes in kidney function but not associated with CKD progression. It is also interesting to note that time to kidney failure onset did not differ between the groups, which may allude to the likelihood of residual confounding or reduced power, given the low number of events.
      Another important consideration that may have influenced the outcomes in the paper by Wetmore et al was the lack of a measure of the quality of anticoagulation in warfarin users; that is, their time in the therapeutic range (TTR). It is well established that a TTR > 70% is associated with improved anticoagulation efficacy and safety, including in individuals with CKD.
      • Bonde A.N.
      • Lip G.Y.H.
      • Kamper A.L.
      • et al.
      Renal function, time in therapeutic range and outcomes in warfarin-treated atrial fibrillation patients: a retrospective analysis of nationwide registries.
      However, attaining an adequate TTR is quite difficult in individuals with CKD owing to a number of factors, including malnutrition and the use of interacting drugs (eg, antibiotics). This is especially the case in individuals with severe CKD where the TTR consistently averages less than 54%.
      • Yang F.
      • Hellyer J.A.
      • Than C.
      • et al.
      Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease.
      Accordingly, the lack of inclusion of a measure of anticoagulation control may have strongly confounded the results to benefit the use of apixaban over warfarin, and also limited any meaningful interpretation as to the etiology of the mechanism of injury that may have been imparted by warfarin. On a similar note, other important factors that may influence the progression of CKD, such as proteinuria, were also not considered, as was also the case with a number of factors that may have influenced apixaban and warfarin pharmacokinetics, including serum albumin values and interacting drugs.
      Finally, the event rates for both outcomes in individuals with stage 4 and 5 CKD were similar to that of individuals with stage 3 CKD. This is unexpected, as individuals with stage 4 and 5 CKD would be at increased risk of adverse events owing to their much more limited kidney reserve. Nevertheless, the wide confidence intervals allude to the uncertainty surrounding this relationship and are likely reflective of the small sample size of individuals with stages 4 and 5 CKD.
      Notwithstanding these issues, the study by Wetmore et al is overall well done and provides another potential reason to use apixaban over warfarin. However, there is already compelling evidence with regard to the superior efficacy and safety of apixaban, compared to warfarin, for the management of atrial fibrillation in individuals with CKD—including those with more severe stages of CKD.
      • Stanifer J.W.
      • Pokorney S.D.
      • Chertow G.M.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation and advanced chronic kidney disease.
      As such, while the possibility of slowing down the progression of CKD is another potentially important benefit of choosing apixaban over warfarin, clinicians have already begun to shift their practice, as demonstrated in the second figure of the article from Wetmore et al. Apixaban is now preferentially used for the management of atrial fibrillation across all strata of CKD, guided by its compelling evidence base and the recommendations of numerous professional bodies. As such, it is inevitable that the use of warfarin will continue to decline—and with that, any potential detrimental kidney effects attributed to it.

      Article Information

      Authors’ Full Names and Academic Degrees

      Ziv Harel, MD, MSc, and Manish M. Sood, MD, MSc.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received February 5, 2021 in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form February 19, 2021.

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