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New Oral Anticoagulants in Elderly Adults With Chronic Kidney Disease

      To the Editor:
      I read with interest the review article by Ponticelli et al
      • Ponticelli C.
      • Sala G.
      • Glassock R.J.
      Drug management in the elderly adult with chronic kidney disease: a review for the primary care physician.
      on drug management in the elderly adult with chronic kidney disease (CKD) that was published in the May 2015 issue of Mayo Clinic Proceedings and agree with their recommendations. Of note, the section on oral anticoagulants does not include or comment on the 4 new oral anticoagulants (NOAs) that have been approved by the US Food and Drug Administration (FDA) over the past 5 years. The NOAs approved are dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and, recently, edoxaban (Savaysa).
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      Atrial fibrillation (AF) is a common disorder in elderly adults. About 12% of AF cases occur in adults 75 to 84 years of age, and more than 33% of patients with AF are 80 years or older. Atrial fibrillation has a global prevalence of about 33.5 million cases and an incidence of approximately 5 million new cases per year. Atrial fibrillation is associated with a 5-fold increased risk of stroke. In the United States, AF accounts for more than 467,000 hospital admissions and more than 99,000 deaths per year.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      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 Practice Guidelines and the Heart Rhythm Society.
      Recently, the NOAs have been gradually replacing warfarin, a vitamin K antagonist that was the standard of care for about 60 years. Thus, I offer a few additional comments for the primary care physician, including the need for renal risk stratification when using the NOAs.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      Typically, the vitamin K antagonist drugs are used for AF in patients with prosthetic heart valves, mitral valve stenosis, severe valvular disease, or severe renal dysfunction, whereas the NOAs are mostly indicated for nonvalvular AF. The field of NOA is evolving, and new indications, boxed warnings, and precautions have been added since their initial approval by the FDA.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      The first NOA approved in the United States was dabigatran, and its approval was based mostly on the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial that randomized participants to either warfarin or 1 of 2 doses of dabigatran (110 mg or 150 mg twice daily).
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      RE-LY Steering Committee and Investigators
      Dabigatran versus warfarin in patients with atrial fibrillation.
      The FDA did not approve the 110-mg dose. The FDA approved the dose of 150 mg twice daily in all patients, including patients with a creatinine clearance of 15 to 30 mL/min per 1.73 m2 (to convert values to mL/s per m2, multiply by 0.0167).
      • Kowey P.R.
      • Naccarelli G.V.
      The Food and Drug Administration decision not to approve the 110 mg dose of dabigatran: give us a way out.
      • Pazmiño P.A.
      Dabigatran: a nephrological way out.
      • Pazmiño P.A.
      Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
      • Pazmiño P.A.
      Dabigatran associated acute renal failure (DAARF).
      This range corresponds to an estimated glomerular filtration rate (eGFR) of 15 to 29 mL/min per 1.73 m2 or a diagnosis of CKD stage 4 (CKD4). This dosing scheme is in stark contrast to doses used in more than 70 countries worldwide, where the 150-mg dose is contraindicated in CKD4.
      • Pazmiño P.A.
      Dabigatran associated acute renal failure (DAARF).
      As in most drug trials, patients with CKD4 were excluded in the RE-LY trial.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      RE-LY Steering Committee and Investigators
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Pazmiño P.A.
      Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
      • Pazmiño P.A.
      Dabigatran associated acute renal failure (DAARF).
      Not surprisingly, 3781 serious adverse effects were noted in the 2011 US postmarketing experience with dabigatran. These events included death (452 cases), hemorrhage (2367 cases), acute renal failure (291 cases), stroke (644 cases), and suspected liver failure (15 cases).
      • Pazmiño P.A.
      Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
      Thirteen months after dabigatran initial approval in the United States, the manufacturer changed the dose and product guidelines. The new dosage is 75 mg twice daily for patients with a creatinine clearance of 15 to 30 mL/min per 1.73 m2 or CKD4.
      • Pazmiño P.A.
      Dabigatran: a nephrological way out.
      • Pazmiño P.A.
      Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
      • Pazmiño P.A.
      Dabigatran associated acute renal failure (DAARF).
      To avoid some of the clinical problems noted with dabigatran, a simple renal risk stratification guideline was proposed that includes the determination of the eGFR that uses serum creatinine for the Modification of Diet in Renal Disease (MDRD) formula and CKD stage.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      The MDRD formula is used by most US laboratories and includes 4 variables: serum creatinine level, age, sex, and race. The MDRD formula is more accurate than the Cockcroft-Gault equation (CGe) described 39 years ago,
      • Levey A.S.
      • Becker C.
      • Inker L.A.
      Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
      which was used in the RE-LY trial. The CGe was developed before the availability of standardized creatinine assays, and it is estimated that its use results in a 10% to 40% overestimate of creatinine clearance. Indirect support for using a renal risk stratification comes from a recent study by Reilly et al.
      • Reilly P.A.
      • Lehr T.
      • Haertter S.
      • et al.
      RE-LY Investigators
      The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
      They reported that renal function was the most important determinant of dabigatran concentration, and age is the most important covariate.
      • Reilly P.A.
      • Lehr T.
      • Haertter S.
      • et al.
      RE-LY Investigators
      The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
      Most US laboratories now provide an eGFR and the stage of CKD.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      Thus, if dabigatran is used, one should follow current manufactures' dosing guidelines for patients with CKD stages 1 through 3, ie, 150 mg twice daily. If CKD4 is detected, the updated recommended dosage is 75 mg twice daily. If the patient has stage 5 CKD (eGFR, <15 mL/min per 1.73 m2), dabigatran is not indicated (Table). Similar steps can be followed for the other NOAs, and we need to adhere to their respective guidelines.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      TableDosing of New Oral Anticoagulants Based on Stage of Chronic Kidney Disease
      bid = twice a day; DVT = deep venous thrombosis; HD = hemodialysis; HR = prophylaxis of DVT following hip replacement; KR = prophylaxis of DVT following knee replacement; NVAF = nonvalvular atrial fibrillation; PE= pulmonary embolism; P-gp = permeability glycoprotein; Rx = treatment.
      Data from Cleve Clin J Med,
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      El Paso Physician,
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      and prescribing information for Pradaxa, Xarelto, Eliquis, and Savaysa. From El Paso Physician,
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      with permission.
      Stages of chronic kidney disease (CKD)Estimated glomerular filtration rate (eGFR)DescriptionDabigatran (Pradaxa) dose for NVAF and DVT/PE
      Dabigatran dose for DVT and PE Rx following 5-10 days of initial Rx with parenteral anticoagulant. It is also approved for RRR (reduction in the risk of recurrence) of DVT and PE for CKD1-3 but not dose provided for CKD4 -5.
      Rivaroxaban (Xarelto) dose for NVAF, DVT/PE
      Xarelto for the Rx of DVT, PE, and RRR dose is 15 mg bid for first 21 days. Thereafter, 20 mg daily.
      /stroke prophylaxis
      Apixaban (Eliquis) dose for NVAF, DVT/PE,
      Eliquis for Rx of DVT and PE: 10 mg bid for 7 days, followed by 5 mg bid. For RRR DVT and PE following initial Rx is 2.5 mg bid.
      and reduction of embolism/stroke treatment
      Edoxaban (Savaysa) dose for NVAF and DVT/PE treatment
      CKD1>90 mL/min per 1.73 m2Renal injury without decreased eGFR150 mg twice daily20 mg daily;

      HR: 10 mg daily

      KR: 10 mg daily
      5 mg bid;

      HR: 2.5 mg bid

      KR: 2.5 mg bid
      eGFR >95: avoid

      eGFR 90-95:

      60 mg daily
      Savaysa dose for DVT and PE: following 5-10 days of initial Rx with parenteral anticoagulant.
      CKD260-89 mL/min per 1.73 m2Mildly decreased eGFR150 mg twice daily20 mg daily;

      HR: 10 mg daily

      KR: 10 mg daily
      5 mg bid;

      HR: 2.5 mg bid

      KR: 2.5 mg bid
      60 mg daily
      Savaysa dose for DVT and PE: following 5-10 days of initial Rx with parenteral anticoagulant.
      CKD330-59 mL/min per 1.73 m2Moderately decreased eGFR150 mg twice daily15 mg daily;

      HR: 10 mg daily

      KR: 10 mg daily
      2.5 mg bid;

      HR: 2.5 mg bid

      KR: 2.5 mg bid
      60 mg daily,
      Savaysa dose for DVT and PE: following 5-10 days of initial Rx with parenteral anticoagulant.


      30 mg daily if used with P-gp inducers
      CKD415-29 mL/min per 1.73 m2Severely decreased eGFR75 mg twice daily15 mg daily;

      HR: 10 mg daily

      KR: 10 mg daily
      2.5 mg bid;

      HR: 2.5 mg bid

      KR: 2.5 mg bid
      30 mg daily
      CKD5<15 mL/min per 1.73 m2Renal failureAvoidAvoidAvoid;

      HD: 2.5-5 mg bid
      Avoid
      a bid = twice a day; DVT = deep venous thrombosis; HD = hemodialysis; HR = prophylaxis of DVT following hip replacement; KR = prophylaxis of DVT following knee replacement; NVAF = nonvalvular atrial fibrillation; PE= pulmonary embolism; P-gp = permeability glycoprotein; Rx = treatment.
      b Dabigatran dose for DVT and PE Rx following 5-10 days of initial Rx with parenteral anticoagulant. It is also approved for RRR (reduction in the risk of recurrence) of DVT and PE for CKD1-3 but not dose provided for CKD4 -5.
      c Xarelto for the Rx of DVT, PE, and RRR dose is 15 mg bid for first 21 days. Thereafter, 20 mg daily.
      d Eliquis for Rx of DVT and PE: 10 mg bid for 7 days, followed by 5 mg bid. For RRR DVT and PE following initial Rx is 2.5 mg bid.
      e Savaysa dose for DVT and PE: following 5-10 days of initial Rx with parenteral anticoagulant.
      If NOAs are to be used in patients with nonvalvular AF, the CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) should be determined. This score gives special attention to congestive heart failure, hypertension, age 75 years and older, diabetes, women, and history of stroke, transient ischemic attack, or systemic embolism.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      A score of 2 is assigned to patients who have a stroke or are 75 years or older. A score of 1 is assigned to each of the remaining risk factors, if present. A total score of 0 requires no treatment, and a score of 2 or more requires treatment. For patients with a score of 1, treatment is decided on an individual basis. Moreover, a renal risk stratification should be done for all NOAs using a comprehensive metabolic panel before treatment begins and 1 week after initiation of the NOA or if there is a change in the patient's clinical condition.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      It should be noted that the suggested dosing of the NOAs based on CKD stages has not been validated for clinical use. However, the actual dosing is the same for equivalent stages of renal dysfunction based on CGe and the current NOA prescribing information.
      The guideline highlights the need for CKD staging to prevent adverse effects.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      As we accumulate more experience with the NOAs, we will have a better understanding of the proper selection of each of these agents. The net clinical benefit
      • Banerjee A.
      • Lane D.A.
      • Torp-Pedersen C.
      • Lip G.Y.
      Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: a modelling analysis based on a nationwide cohort study.
      obtained should be evaluated with each agent in this upcoming era of individualized patient care and precision medicine. The NOAs can be a welcome addition to our armamentarium to treat patients who need anticoagulation. Because of the narrow therapeutic indices of the NOAs,
      • Powell R.J.
      Are new oral anticoagulant dosing recommendations optimal for all patients?.
      use of the proposed renal risk stratification is suggested to avoid some of the risks, morbidity, mortality, and expense in managing serious NOA adverse effects.
      • Pazmiño P.
      Renal risk stratification with the new oral anticoagulants.
      • Pazmiño P.
      The need for renal risk stratification when using the new oral anticoagulants.
      • Pazmiño P.A.
      Dabigatran: a nephrological way out.
      • Pazmiño P.A.
      Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
      • Pazmiño P.A.
      Dabigatran associated acute renal failure (DAARF).

      References

        • Ponticelli C.
        • Sala G.
        • Glassock R.J.
        Drug management in the elderly adult with chronic kidney disease: a review for the primary care physician.
        Mayo Clin Proc. 2015; 90: 633-645
        • Pazmiño P.
        Renal risk stratification with the new oral anticoagulants.
        Cleve Clin J Med. 2013; 80 ([letter]): 733-734
        • Pazmiño P.
        The need for renal risk stratification when using the new oral anticoagulants.
        El Paso Physician. 2015; 38: 7-9
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • et al.
        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 Practice Guidelines and the Heart Rhythm Society.
        J Am Coll Cardiol. 2014; 64: e1-e76
      1. Pradaxa [package insert]. Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CTMarch 2011 and April 2013
      2. Xarelto [package insert]. Janssen Pharmaceuticals, Inc, Titusville, NJMarch 2013
      3. Eliquis [package insert]. Bristol-Myers Squibb Company, Princeton, NJDecember 2012
      4. Savaysa [package insert]. Daiichi Sankyo Company, Limited, Parsippany, NJApril 2015
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        • RE-LY Steering Committee and Investigators
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361 ([published correction appears in N Engl J Med. 2010;363(19):1877]): 1139-1151
        • Kowey P.R.
        • Naccarelli G.V.
        The Food and Drug Administration decision not to approve the 110 mg dose of dabigatran: give us a way out.
        Am J Med. 2012; 125 ([editorial]): 732
        • Pazmiño P.A.
        Dabigatran: a nephrological way out.
        Am J Med. 2013; 126 ([letter]): e21
        • Pazmiño P.A.
        Dabigatran side effects: nephrological perspective and opinion. [letter]. Comments in Dabigatran: Uncharted Waters and Potential Harms.
        Ann Intern Med. 2012; 157: 66-68
        • Pazmiño P.A.
        Dabigatran associated acute renal failure (DAARF).
        El Paso Physician. 2011; 34: 7-9
        • Levey A.S.
        • Becker C.
        • Inker L.A.
        Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
        JAMA. 2015; 313: 837-846
      5. Inker LA, Perrone RD. Assessment of kidney function. UpToDate website. http://www.uptodate.com/contents/assessment-of-kidney-function?source=search_result&search=Assessment+of+kidney+function&selectedTitle=1∼150. Accessed June 24, 2015.

        • Reilly P.A.
        • Lehr T.
        • Haertter S.
        • et al.
        • RE-LY Investigators
        The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy).
        J Am Coll Cardiol. 2014; 63: 321-328
        • Banerjee A.
        • Lane D.A.
        • Torp-Pedersen C.
        • Lip G.Y.
        Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: a modelling analysis based on a nationwide cohort study.
        Thromb Haemost. 2012; 107: 584-589
        • Powell R.J.
        Are new oral anticoagulant dosing recommendations optimal for all patients?.
        JAMA. 2015; 313: 1013-1014

      Linked Article

      • Drug Management in the Elderly Adult With Chronic Kidney Disease: A Review for the Primary Care Physician
        Mayo Clinic ProceedingsVol. 90Issue 5
        • Preview
          With advancing age, the functional reserve of many organs tends to decrease. In particular, the lean body mass, the levels of serum albumin, the blood flow to the liver, and the glomerular filtration rate are reduced in elderly individuals and can be further impaired by the concomitant presence of acute or chronic kidney disease. Moreover, patients with kidney disease are often affected by comorbid processes and are prescribed multiple medications. The aging process also modifies some drug interactions, including the affinity of some drugs for their receptor, the number of receptors, and the cell responses upon receptor activation.
        • Full-Text
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      • In reply—New Oral Anticoagulants in Elderly Adults With Chronic Kidney Disease
        Mayo Clinic ProceedingsVol. 90Issue 11
        • Preview
          We thank Dr Pazmiño for his comments on our article. Many of the new oral anticoagulants (NOAs) are excreted to a substantial extent by the kidney, and it is certainly necessary to consider dosage adjustments on the basis of the patient's estimated glomerular filtration rate. It is true that the occurrence of nonvalvular atrial fibrillation is increased in patients with advanced kidney failure, and use of NOAs has some appeal for this condition compared with other oral anticoagulants such as vitamin K antagonists (warfarin).
        • Full-Text
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