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American Journal of Kidney Diseases

Anticoagulation for Stroke Prevention in Atrial Fibrillation

  • Nicolas Krepostman
    Affiliations
    Department of Medicine, Loyola University Chicago, Maywood, Illinois
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  • Holly J. Kramer
    Correspondence
    Address for Correspondence: Holly J. Kramer, MD, MPH, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153.
    Affiliations
    Department of Medicine, Loyola University Chicago, Maywood, Illinois

    Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, Illinois

    Department of Public Health Science, Loyola University Chicago, Maywood, Illinois
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Published:September 01, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.06.003
      Related Article, p. 569
      According to Dr Christian Busch, author of The Serendipity Mindset, life-changing random opportunities cross our paths multiple times during our lifetime, but most of these lucky breaks go unrecognized.
      • Busch C.
      The Serendipity Mindset: The Art and Science of Creating Good Luck.
      In 1933, chance favored Dr Karl Link when he unexpectedly encountered a frustrated farmer, Ed Carlson, who had driven 200 miles during a blizzard with a dead cow in the back of his truck.
      • Wardrop D.
      • Keeling D.
      The story of the discovery of heparin and warfarin.
      Hemorrhagic cow disease linked with consumption of moldy sweet clover had decimated his herd, and as a Depression-era farmer facing economic hardship, he was desperate for help. Link recognized the life-changing opportunity that Carlson provided and immediately began the hunt for the cow-killing anticoagulant. With funding from the Wisconsin Alumni Research Foundation, Link eventually isolated an antithrombotic substance that came to be called dicoumaril from moldy hay and then, later, synthesized the more rapidly acting antithrombotic variant warfarin, which he developed as a rodenticide in 1945. By the 1950s, warfarin, marketed as Coumadin, was introduced as an anticoagulant for humans. One of the first beneficiaries was President Eisenhower, who was treated with the drug after his myocardial infarction in 1955.
      • Wardrop D.
      • Keeling D.
      The story of the discovery of heparin and warfarin.
      Warfarin effectively reduces stroke risk in adults with nonvalvular atrial fibrillation (AF), but the 2019 update of the AHA/ACC/HRS 2014 guideline for management of patients with AF now recommends direct oral anticoagulants (DOACs) such as apixaban, a factor Xa inhibitor, as first-line therapy for the prevention of stroke and thromboembolism in adults with nonvalvular AF, except in patients with moderate-to-severe mitral stenosis or a mechanical heart valve.
      • January C.T.
      • Wann L.S.
      • 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.
      Warfarin requires frequent drug monitoring, whereas DOACs do not. Unfortunately for patients receiving dialysis, adults with an estimated creatinine clearance ≤25 mL/min were excluded from all phase 3 trials of DOACs
      • January C.T.
      • Wann L.S.
      • 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.
      and warfarin has never been shown to conclusively reduce stroke risk or mortality in adults with kidney failure.
      • Reinecke H.
      • Jürgensmeyer S.
      • Engelbertz C.
      • et al.
      Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.
      Owing to lack of evidence, the decision to anticoagulate and the anticoagulant choice for patients with nonvalvular AF receiving maintenance dialysis remain the burden of the treating clinician. The 2019 ACC/AHA/HRS guideline update states that use of warfarin with an international normalized ratio (INR) goal of 2.0-3.0 or apixaban is a reasonable approach for treating patients receiving maintenance dialysis with AF, but this statement is based on moderate-quality evidence from meta-analyses of observational or nonrandomized studies and registries, and is classified as a weak recommendation.
      • January C.T.
      • Wann L.S.
      • 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.
      Several randomized clinical trials have been designed to compare the benefits and risks of apixaban versus warfarin in patients receiving maintenance dialysis with AF. For example, SAFE-D (Clinicaltrials.gov identifier NCT03987711) is evaluating DOACs versus warfarin versus no anticoagulation for the management of nonvalvular AF in patients receiving maintenance dialysis. AXADIA-AFNET 8 (Clinicaltrials.gov identifier NCT02933697) is comparing apixaban versus the vitamin K antagonist phenprocoumon with a goal INR of 2-3.0.
      • Reinecke H.
      • Jürgensmeyer S.
      • Engelbertz C.
      • et al.
      Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.
      The RENAL-AF trial (Clinicaltrials.gov identifier NCT02942407) was terminated prematurely in 2019 owing to low enrollment and remains unpublished.
      In 2014, the US Food and Drug Administration (FDA) extended the use of apixaban to patients receiving maintenance dialysis based on pharmacokinetic data.
      US Food and Drug Administration
      Eliquis (apixaban) Tablets.
      • Wang X.
      • Tirucherai G.
      • Marbury T.C.
      • et al.
      Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.
      • Chang M.
      • Yu Z.
      • Shenker A.
      • et al.
      Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
      Currently, the recommended dose of apixaban for patients receiving maintenance dialysis is 5 mg twice daily but should be reduced to 2.5 mg twice daily for patients with age ≥80 years or weight ≤60 kg.
      US Food and Drug Administration
      Eliquis (apixaban) Tablets.
      Apixaban is sometimes prescribed at reduced dose for patients receiving maintenance dialysis owing to concerns of bleeding, but a discordant dosing strategy may lead to more harm than benefit if a reduced dose does not reduce stroke risk or mortality.
      In this issue of AJKD, Wetmore et al
      • Wetmore J.B.
      • Weinhandl E.D.
      • Yan H.
      • Reyes J.L.
      • Herzog C.A.
      • Roetker N.S.
      Apixaban dosing patterns versus warfarin in patients with nonvalvular atrial fibrillation receiving dialysis: a retrospective cohort study.
      present results from a retrospective cohort study that examined patient outcomes with nonvalvular AF treatment with warfarin versus apixaban at different doses among patients receiving maintenance dialysis who do not meet criteria for reduced apixaban dosing. Using data from the US Renal Data System, investigators identified adults with a diagnosis code for nonvalvular AF who initiated either warfarin or apixaban between April 2013 and December 2018. The analysis excluded patients prescribed anticoagulants 6 months prior to the index date or required anticoagulation for conditions other than nonvalvular AF, and those who met criteria for reduced apixaban dosing (age ≥80 years and/or weight ≤60 kg). Major bleeding outcomes included fatal events, bleeding from a critical site, or blood transfusion requirement. To address the observational study design, inverse probability of treatment weighting was used so that groups treated with different drugs or drug doses would be otherwise similar with regard to demographics and comorbidities. As with an intention-to-treat analysis, patients were followed until death, loss of Medicare coverage, change of dialysis modality, kidney transplantation, or loss to follow-up, regardless of medication change or discontinuation. The investigators also constructed models that censored patients when the anticoagulant was discontinued or changed in order to mimic an as-treated analysis.
      Among the 17,156 identified patients with nonvalvular AF, 73% were prescribed warfarin, 13.9% were prescribed a label-concordant apixaban dose, and 13.1% were prescribed a below-label apixaban dose. Compared to warfarin, both label-concordant (hazard ratio [HR], 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban were associated with lower risk of major bleeding in the intention-to-treat analysis and findings were similar in analyses that censored at drug discontinuation or drug change. This study found no difference in bleeding risk with below-label versus label-concordant apixaban (HR, 1.02 [95% CI, 0.78-1.34]) and no difference in risk of stroke or systemic embolism with label-concordant (HR, 0.89 [95% CI, 0.65-1.21]) or below-label (HR, 0.85 [95% CI, 0.62-1.17]) apixaban compared to warfarin in the intention-to-treat analyses. However, mortality risk was significantly lower with label-concordant apixaban compared to warfarin (HR, 0.85 [95% CI, 0.78-0.92]) but not with below-label apixaban (HR, 0.97 [95% CI, 0.89-1.05]) compared to warfarin. Similar findings were noted in analyses that censored at drug discontinuation or drug change.
      • Wetmore J.B.
      • Weinhandl E.D.
      • Yan H.
      • Reyes J.L.
      • Herzog C.A.
      • Roetker N.S.
      Apixaban dosing patterns versus warfarin in patients with nonvalvular atrial fibrillation receiving dialysis: a retrospective cohort study.
      It is important that Wetmore et al conducted analyses that address the dynamics of medication use in patients receiving dialysis. As shown in their Table S6, more than half of all patients in this study discontinued the prescribed anticoagulant regardless of drug or dose. The average follow-up time before the anticoagulant was discontinued or changed was 208 days for warfarin, 154 days for label-concordant apixaban, and 165 days for below-label apixaban, while the follow-up times for the intention-to-treat analyses for these groups were 614, 656, and 412 days, respectively. Thus, many patients are discontinuing the initially prescribed anticoagulant within 1 year.
      A similar observational study of Medicare beneficiaries receiving maintenance dialysis during the years 2010-2015 also reported significantly lower risk of stroke or systemic embolism with apixaban 5 mg twice daily versus apixaban 2.5 mg twice daily (HR, 0.61 [95% CI, 0.37-0.98]) and versus warfarin (HR, 0.64 [95% CI, 0.42-0.97]).
      • Siontis K.C.
      • Zhang X.
      • Eckard A.
      • et al.
      Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.
      Although this study showed a nonsignificant reduction in mortality rate with apixaban compared to warfarin (HR, 0.85 [95% CI, 0.71-1.01]), analyses stratified by apixaban dose reported significantly lower mortality risk with apixaban 5 mg compared to the 2.5 mg dose (HR, 0.64 [95% CI, 0.45-0.92]) and compared to warfarin (HR, 0.64 [95% CI, 0.45-0.92]). A smaller observational study of patients with AF receiving maintenance dialysis used propensity score matching to compare outcomes among 521 treated with apixaban versus 1,561 with no anticoagulation. This study found significantly higher risk of ischemic and hemorrhagic stroke and thromboembolism with apixaban use versus no anticoagulation, but significant associations were limited to the 5 mg (HR, 2.24 [95% CI, 1.03-4.86]) and not the 2.5 mg (HR, 1.11 [95% CI, 0.43-2.85]) apixaban dosing regimen.
      • Mavrakanas T.A.
      • Garlo K.
      • Charytan D.M.
      Apixaban versus no anticoagulation in patients undergoing long-term dialysis with incident atrial fibrillation.
      The substantially higher risk of ischemic strokes in the treated group may have been due to residual confounding by indication whereby healthier patients with lower risk of stroke were not prescribed anticoagulation.
      The study by Wetmore et al was limited by the exclusion of patients who met FDA indications for reduced-dose apixaban (age >80, weight <60 kg). Use of administrative claims data to identify outcomes could have also introduced misclassification, and analyses did not include a comparison of outcomes with no treatment. The study is also observational and cannot fully control for the heterogeneity of patient characteristics that exist between patients prescribed apixaban versus warfarin. Regardless of these limitations, this study adds to the accumulating data on the safety of apixaban dosing regimens. Prescribing lower-dose DOACs for AF treatment in patients receiving maintenance dialysis to lower bleeding risk as suggested by a KDIGO controversies conference report
      • Wanner C.
      • Herzog C.A.
      • Turakhia M.P.
      Conference Steering Committee. Chronic kidney disease and arrhythmias: highlights from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
      may possibly be myopic if mortality risk is substantially lower with prescribed label-concordant dosing strategies. Until ongoing clinical trials are completed, the uncertainty of the risks and benefits of anticoagulation in a population with an unpredictable response to treatment means that treatment decisions will need to be made on an individual basis.
      • Wanner C.
      • Herzog C.A.
      • Turakhia M.P.
      Conference Steering Committee. Chronic kidney disease and arrhythmias: highlights from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
      As William Osler noted, “Medicine is a science of uncertainty and an art of probability.”
      • Bean W.B.
      Sir William Osler: aphorisms from his bedside teaching and his writings.

      Article Information

      Authors’ Full Names and Academic Degrees

      Nicolas Krepostman, MD, and Holly J. Kramer, MD, MPH.

      Support

      None.

      Financial Disclosure

      Dr Kramer has received consulting fees from Bayer Pharmaceuticals and Astra Zeneca. Dr Krepostman declares that he has no relevant financial interests.

      Peer Review

      Received April 19, 2022, in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form June 22, 2022.

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