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Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients Taking RAAS Inhibitors
Accepted Manuscript Title: Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients on Renin-Angiotensin-Aldosterone-System Inhibitors Author: Matthew R. Weir, David A. Bushinsky, Wade W. Benton, Steven D. Woods, Martha R. Mayo, Susan P. Arthur, Bertram Pitt, George L. Bakris PII: DOI: Reference:
S0002-9343(17)31203-2 https://doi.org/10.1016/j.amjmed.2017.11.011 AJM 14394
To appear in:
The American Journal of Medicine
Please cite this article as: Matthew R. Weir, David A. Bushinsky, Wade W. Benton, Steven D. Woods, Martha R. Mayo, Susan P. Arthur, Bertram Pitt, George L. Bakris, Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients on Renin-AngiotensinAldosterone-System Inhibitors, The American Journal of Medicine (2017), https://doi.org/10.1016/j.amjmed.2017.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease
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Patients on Renin-Angiotensin-Aldosterone-System Inhibitors
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Matthew R. Weir, MD;a David A. Bushinsky, MD;b Wade W. Benton, PharmD;c Steven
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D. Woods, PharmD;c Martha R. Mayo, PharmD;c Susan P. Arthur, PhD;c Bertram Pitt,
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MD;d George L. Bakris, MDe
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a
Division of Nephrology, Department of Medicine, University of Maryland School of
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Medicine, 22 S. Greene St., Room N3W143, Baltimore, MD, USA, 21201;
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[email protected];
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b
Division of Nephrology, Department of Medicine, University of Rochester School of
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Medicine, 601 Elmwood Ave., Box 675, Rochester, NY, USA, 14642;
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[email protected];
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c
Relypsa, Inc., a Vifor Pharma Group Company, 100 Cardinal Way, Redwood City, CA,
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USA, 94063; [email protected]; [email protected]; [email protected];
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[email protected];
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d
Department of Internal Medicine, University of Michigan School of Medicine, 1500 East
Medical Center Drive, Ann Arbor, MI, USA, 48109; [email protected]; e
Comprehensive Hypertension Center, Department of Medicine, University of Chicago
Medicine, 5841 S Maryland Ave, Chicago, IL, USA, 60637; [email protected];
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Corresponding Author: Matthew R. Weir, MD Professor and Director Division of Nephrology University of Maryland School of Medicine 22 S. Greene St., Room N3W143 Baltimore, MD 21201 USA Tel: +1 410-328-5720 Fax +1 410-328-5685 Email: [email protected]
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Funding: This study was funded by Relypsa, Inc., a Vifor Pharma Group Company 1 Page 1 of 39
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Conflict-of-Interest Statement: Dr. Weir reports personal fees for scientific advisory
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boards from Relypsa, Inc. and Vifor Pharma Management Ltd., both Vifor Pharma
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Group Companies; and from ZS Pharma, Akebia, Janssen, AstraZeneca, Sanofi, MSD,
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AbbVie, and Boston Scientific outside the submitted work. Dr. Bushinsky reports
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personal fees from and past stock ownership of Relypsa, Inc., a Vifor Pharma Group
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Company; personal fees outside the submitted work from Amgen, Sanofi/Genzyme,
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OPKO, and Tricida; and stock outside of the submitted work in Amgen and Tricida. He
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reports research support from the National Institutes of Health and from the Renal
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Research Institute outside of the submitted work. Drs. Mayo, Woods, and Arthur
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report employment by and past stock ownership of Relypsa, Inc., a Vifor Pharma Group
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Company. Dr. Benton reports employment by Relypsa, Inc., a Vifor Pharma Group
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Company, when the study was conducted. Dr. Pitt reports personal fees for consulting
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with Sanofi, Relypsa, Inc., a Vifor Pharma Group Company, Merck, Bayer,
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AstraZeneca, Boehringer Ingelheim, Forest Laboratories, scPharmaceuticals,
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PharMain, Tricida, DaVinci Therapeutics, KBP Biosciences, Stealth Peptides, and
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AuraSense. He has stock options with scPharmaceuticals, PharMain, DaVinci
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Therapeutics, Tricida, KBP Biosciences, and AuraSense. He serves on a data safety
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monitoring committee for and receives personal fees from Johnson & Johnson,
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Novartis, and Tenax Pharmaceuticals. He serves on a clinical events committee and
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receives personal fees from Juventas Therapeutics. In addition, he has a pending
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patent EFS ID 14916043, application number 61762661/UM-33001/US-1PRO, for the
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site-specific delivery of eplerenone to the myocardium. Dr. Bakris reports personal fees
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and other from Relypsa, Inc., a Vifor Pharma Group Company; grants from AbbVie,
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Janssen, and Bayer.
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All authors had access to the data and a role in writing the manuscript.
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Journal: American Journal of Medicine (type: Clinical Research Study)
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Key Words: Chronic kidney disease; RAASi; Patiromer; Aging
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Running Head: Patiromer Lowers Serum K+ in Older Chronic Kidney Disease Patients
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Number of Words (Abstract): 266 of 250 allowed
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Number of Words (Total): 3381 of 3000 allowed (including text, and acknowledgement
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but NOT including abstract, tables, references, clinical significance, or title page)
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CLINICAL SIGNIFICANCE (69 words of 70 allowed)
predisposed to risk of hyperkalemia.
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Because of age, comorbidity, and polypharmacy, older patients are particularly
Patiromer significantly decreased serum K+ in hyperkalemic patients aged ≥65
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years with chronic kidney disease on RAASi and reduced the risk of recurrent
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hyperkalemia.
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RAASi medications compared with those on placebo.
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A significantly larger proportion of patients on patiromer continued to receive
Patiromer was well tolerated in patients aged ≥65 years and <65 years.
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ABSTRACT (266 of 250 allowed)
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Background: Older people are predisposed to hyperkalemia because of impaired renal
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function, comorbid conditions, and polypharmacy. Renin-angiotensin-aldosterone
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system inhibitors (RAASi), guideline-recommended for the treatment of chronic kidney
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disease and heart failure, further augment the risk. Patiromer, a nonabsorbed
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potassium binder, was shown in a phase 3 study (OPAL-HK) to decrease serum
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potassium in patients with chronic kidney disease on RAASi. We studied the efficacy
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and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from
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OPAL-HK.
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Methods: Chronic kidney disease patients with mild or moderate-to-severe
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hyperkalemia received patiromer, initially 8.4 g/day or 16.8 g/day, respectively, for 4
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weeks (treatment phase, Part A). Eligible patients entered an 8-week randomized
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withdrawal phase (Part B) and either continued patiromer or switched to placebo.
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Results: The mean ± standard error change in serum potassium from baseline to week
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4 of Part A (primary endpoint) in patients ≥65 years was −1.01 ± 0.05 mEq/L (P <0.001);
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97% achieved normokalemia (serum potassium 3.8–<5.1 mEq/L). The increase in
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serum potassium during the first 4 weeks of Part B was significantly greater in patients
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on placebo than in those on patiromer (P <0.001). Significantly fewer patients on
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patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum
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potassium ≥5.1 mEq/L). The most common adverse event in patients ≥65 years was
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mild-to-moderate constipation (15% in Part A, 7% in Part B). Serum potassium <3.5
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mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients ≥65
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years in Part A).
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Conclusions: Patiromer reduced serum potassium and recurrent hyperkalemia, and
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was well tolerated in older patients with chronic kidney disease on RAASi. INTRODUCTION
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The number of US adults aged ≥65 years is expected to increase from 420 million in
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2000 to 973 million (12.0%) in 2030.1 Advancing age is associated with increased
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prevalence of chronic conditions such as chronic kidney disease, heart failure,
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hypertension, and diabetes.2,3 Together, aging and chronic conditions contribute to
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increased hospitalizations, medical interventions, and use of long-term care services,
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thereby significantly increasing the economic burden on the healthcare system.4–8 In several clinical studies, use of renin-angiotensin-aldosterone system inhibitors
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(RAASi) has been shown to slow the progression of diabetic and nondiabetic chronic
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kidney disease9–12 and to reduce morbidity and mortality in patients with heart failure.13–
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American and European guidelines recommend RAASi for the treatment of these
conditions.19–24 RAASi prescribed at the maximum recommended dose, compared with
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submaximal doses, may improve clinical outcomes and reduce total costs.25,26 However,
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RAASi use increases hyperkalemia risk, especially in older patients with reduced
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aldosterone production, reduced glomerular filtration rate (GFR), and impaired renal
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tubular function.27–31
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Hyperkalemia can lead to life-threatening aberrations in cardiac conduction,
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arrhythmias, and sudden death.28,31,32 RAASi-induced hyperkalemia is associated with
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increased risk of adverse renal outcomes and mortality in patients with chronic kidney
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disease.31,33,34 Physicians may discontinue or reduce the RAASi dose, or they may not
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initiate RAASi, due to hyperkalemia concerns.35 Retrospective analysis of medical
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records of patients with chronic kidney disease, heart failure, or diabetes suggests that
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maximum doses of RAASi are either discontinued or dose-reduced almost 50% of the
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time following a moderate-to-severe hyperkalemic event.36 Lowering serum potassium
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(K+) levels in hyperkalemic patients on RAASi may improve clinical outcomes by
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prevention of hyperkalemia-associated cardiac adverse effects and allowing
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continuation of guideline-recommended RAASi therapy.37,38
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Patiromer (Veltassa®; Relypsa, Inc., a Vifor Pharma Group Company, Redwood
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City, CA), a nonabsorbed, sodium-free K+-binder that acts predominantly in the colon
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and uses calcium as the counter-exchange ion,39 is approved in the US and the EU for
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the treatment of hyperkalemia.40,41 Patiromer has been demonstrated to be effective in
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lowering serum K+ levels and generally safe in hyperkalemic patients with chronic
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kidney disease on RAASi, many of whom also had heart failure, diabetes, and/or
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hypertension.37,42–44 In the phase 3 OPAL-HK trial, patiromer significantly decreased the
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rate of recurrent hyperkalemia.43 Here, we studied the efficacy and safety of patiromer
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in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.
141 142
METHODS
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Study Design and Patient Population
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The OPAL-HK study has been described previously.43 Briefly, 243 patients were
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enrolled in a 4-week initial treatment phase (Part A). Eligible patients were adults (18–
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80 years old) with chronic kidney disease stage 3 or 4 (estimated GFR [eGFR] 15–<60
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mL/min/1.73 m2) and hyperkalemia (serum K+ 5.1–<6.5 mEq/L by local laboratory
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measurement) who were on a stable dose of ≥1 RAASi medications for ≥28 days at
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screening.
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At the beginning of Part A, patients with mild hyperkalemia (serum K+ 5.1–<5.5
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mEq/L) at screening were assigned to patiromer 8.4 g/day; those with moderate-to-
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severe hyperkalemia (5.5–<6.5 mEq/L) were assigned to patiromer 16.8 g/day (all
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doses were given BID). The patiromer dose was adjusted according to a prespecified
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titration algorithm to maintain serum K+ within the range of 3.8–<5.1 mEq/L. During this
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phase, RAASi therapy was not allowed to be adjusted unless medically necessary but
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could be discontinued if serum K+ was ≥6.5 mEq/L (or ≥5.1 mEq/L for patients on
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maximum patiromer dose).
158
Patients who had serum K+ ≥5.5 mEq/L at baseline of Part A and were
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normokalemic (serum K+ 3.8–<5.1 mEq/L), while receiving patiromer and on ≥1 RAASi
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medications at the end of Part A, were eligible to enter Part B (8-week placebo-
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controlled randomized withdrawal phase). Patients meeting these criteria (n = 107) were
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randomized 1:1 to continue patiromer at the daily dose they were receiving at week 4 of
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Part A or to switch to placebo. Recurrence of hyperkalemia (serum K+ ≥5.5 mEq/L)
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during Part B was managed with a prespecified algorithm as described previously.43
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Laboratory assessments, conducted at baseline (day 1), day 3 of each phase,
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and weekly thereafter, included serum K+ and serum chemistry (including creatinine and
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eGFR). Sitting blood pressure was measured in triplicate at each visit.
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Efficacy and Safety Assessments
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Analysis of the primary efficacy endpoints for Part A and Part B were prespecified by
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age (≥65 years, <65 years): Part A, change in serum K+ from baseline to week 4 of the
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initial treatment phase; Part B, between group difference in change in serum K+ from
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start to week 4 of the randomized withdrawal phase. During the first 4 weeks of Part B,
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changes in patiromer or RAASi doses were not permitted unless serum K + was ≥5.5
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mEq/L in order to facilitate interpretation of the primary endpoint (see the online
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supplement to Weir et al43 for details). Analysis of the secondary efficacy endpoint in
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Part B was prespecified by age group: proportion of patients with serum K+ ≥5.5 mEq/L
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and serum K+ ≥5.1 mEq/L at any time during Part B.43
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Other efficacy endpoints were assessed post-hoc by age group, including: Part
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A, proportion of patients with serum K+ in the normal range (3.8–<5.1 mEq/L) at any
181
time; and Part B, time to recurrent hyperkalemia; time to RAASi discontinuation;
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proportion of patients requiring intervention to manage hyperkalemia (defined as
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patiromer dose increase or RAASi discontinuation for patients on patiromer and RAASi
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dose decrease of ≥50% or RAASi discontinuation for patients on placebo); and
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proportion of patients on RAASi at the end of the withdrawal phase. +
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Safety was evaluated in each age group by adverse events, change in blood
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pressure, change in serum magnesium (Mg2+), and proportions of patients with serum
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Mg2+ <1.4 mg/dL or serum K+ <3.5 mEq/L.
189 190
Statistical Analyses
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Initial treatment phase (Part A)
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Mean change in serum K+ from baseline to week 4 was assessed in enrolled patients
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who received ≥1 dose of patiromer and had ≥1 post-baseline weekly serum K+
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measurement. The mean changes in serum K+ (± standard error [SE]) and 95%
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confidence intervals (CIs) were estimated separately by age group using longitudinal
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repeated-measures models that included presence or absence of heart failure,
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presence or absence of type 2 diabetes, and baseline serum K+.
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Randomized withdrawal phase (Part B)
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Change in serum K+ at week 4 or first local serum K+ <3.8 or ≥5.5 mEq/L was compared
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between treatment groups, separately for each age group, using ranked values of
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change in serum K+ and an analysis of variance (ANOVA) model that included
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treatment group, level of serum K+ at the start of the initial treatment phase (<5.8 mEq/L
204
or ≥5.8 mEq/L), and presence or absence of type 2 diabetes. The difference and 95%
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CI between the treatment groups in median change from baseline were estimated,
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within age group, using a Hodges-Lehmann estimator.
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Proportions of subjects with recurrent hyperkalemia (serum K+ ≥5.5 mEq/L and
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≥5.1 mEq/L) at any time during the withdrawal phase were stratified by serum K + level
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at the start of the initial phase of the study (<5.8 mEq/L or ≥5.8 mEq/L) and by presence
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or absence of type 2 diabetes. Treatment groups were compared, separately by age
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group, using the Mantel-Haenszel test.
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Kaplan-Meier methods were used to estimate the time to recurrent hyperkalemia
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and time to discontinuation of RAASi during the withdrawal phase. Additional details
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regarding statistical methods were published previously.43
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RESULTS
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Patient Disposition
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Of patients enrolled in Part A, 131 (54%) were aged ≥65 years and 112 (46%) <65
219
years; 87% and 94%, respectively, completed Part A. The two most common reasons
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for discontinuation were adverse events (7 [5%] ≥65 years and 3 [3%] <65 years) and
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consent withdrawal (4 [3%] and 1 [1%], respectively).
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Of 107 patients who met eligibility criteria to enter Part B, 60 (56%) were ≥65
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years and 47 (44%) were <65 years. Among patients who completed Part A, the most
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common reason for ineligibility for Part B was serum K+ level <5.5 mEq/L at baseline of
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Part A (48 [42%] ≥65 years and 49 [47%] <65 years). A total of 40 (67%) patients ≥65
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years (22/29 [76%] on patiromer and 18/31 [58%] on placebo) and 35 (74%) patients
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<65 years (23/26 [88%] on patiromer and 12/21 [57%] on placebo) completed the study.
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The most common reason for discontinuation was high serum K+ level meeting protocol-
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specified withdrawal criterion, occurring in 2 patients (4%) on patiromer and 14 (27%)
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on placebo.
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Baseline Demographic and Clinical Characteristics in Part A
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Mean (standard deviation [SD]) age was 71.7 (4.4) years for patients ≥65 years, and
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55.5 (8.6) years for those <65 years (Table 1). Approximately 24% of patients ≥65 years
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and 29% <65 years had stage 3B chronic kidney disease; 43% and 47%, respectively,
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had stage 4/5 chronic kidney disease (Table 1). There was no difference in mean (SD)
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eGFR between the two subgroups, whereas serum creatinine was lower in patients ≥65
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years (P <0.01; Table 1). Heart failure was presentin 52% of patients ≥65 years and in
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30% of those <65 years. The mean (SD) serum K+ was similar by age group (≥65 years:
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5.59 [0.54] mEq/L, <65 years: 5.56 [0.49] mEq/L). Patients ≥65 years were taking 6.7
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concomitant medications on average at baseline, and those <65 years were taking 5.8;
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all were on RAASi medications (primarily ACE inhibitors) and a majority were taking
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non-RAASi, nondiuretic antihypertensives and non-RAASi diuretics. (Supplementary
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Table 1).
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Efficacy
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Initial treatment phase (Part A)
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The estimated mean ± SE change in serum K+ from baseline to week 4 in patients who
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received ≥1 dose of patiromer and had ≥1 serum K+ measurement after day 3 was
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−1.01 ± 0.05 mEq/L (95% CI, −1.10, −0.92) for patients ≥65 years (n = 126) and −0.96 ±
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0.05 mEq/L (−1.05, −0.88) for those <65 years (n = 111; P <0.001 for both); P=0.50 for
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difference between age groups. The estimated mean ± SE serum K+ for patients ≥65
253
years and <65 years during Part A is shown in Figure 1.
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Among patients with ≥1 centrally measured serum K+ value after baseline, the
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proportion that achieved normokalemia (serum K+ 3.8–<5.1 mEq/L) at any time during
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Part A was 97%, both for patients ≥65 years (122/126) and for those <65 years
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(108/111).
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The mean daily dose of patiromer during Part A was 17.5 g in patients ≥65 years
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and 19.0 g in patients <65 years. Of the 78/131 patients ≥65 years and the 69/112
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patients <65 years who required a dose adjustment, the majority (53 [68%] and 38
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[55%], respectively) required only one adjustment.
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Randomized withdrawal phase (Part B)
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Mean (SD) serum K+ for patients ≥65 years who entered Part B was 4.51 (0.42) mEq/L.
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During the first 4 weeks of this phase, serum K+ levels remained stable in patiromer-
266
treated patients and increased in placebo-treated patients. Differences between the
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patiromer vs placebo groups in the median (95% CI) change in serum K+ were 0.81
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(0.49, 1.14) mEq/L (P <0.001) in patients ≥65 years and 0.57 (0.11, 1.03) mEq/L (P =
269
0.006) in patients <65 years (Supplementary Figure 1).
270
Among patients aged ≥65 years on patiromer vs placebo, 11% vs 64% (P
271
<0.001) had at least one serum K+ value ≥5.5 mEq/L and 30% vs 92% (P <0.001) had
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at least one serum K+ value ≥5.1 mEq/L (Figure 2). Results for patients <65 years were
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generally similar, although the difference between treatment groups in the proportion
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with serum K+ ≥5.1 mEq/L was more pronounced in the older vs the younger age group
275
(P <0.05) (Figure 2). The time to first recurrence of hyperkalemia is shown in
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Supplementary Figure 2 (Panels A and B, time to first serum K+ level >5.5 mEq/L;
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Panels C and D, time to first serum K+ level >5.1 mEq/L).
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The proportion of patients ≥65 years who required an intervention to manage
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hyperkalemia was 10% for patiromer vs 71% for placebo (Figure 3A). All patients ≥65
280
years (100%) receiving patiromer, compared with 48% of those on placebo, continued
281
to be on RAASi at the end of Part B (Figure 3B). Results for patients <65 years were
282
similar (Figure 3). Time to RAASi discontinuation is shown in Figure 4.
283
During Part A, mean daily patiromer doses were similar in patients subsequently
284
randomized to continue patiromer (18.7 g/day for those ≥65 years and 21.6 g/day for
285
those <65 years) or to switch to placebo (21.2 g/day for both patients ≥65 and <65
286
years). During Part B, the mean daily dose in the patiromer group was 19.9 g/day in
287
patients ≥65 years and 22.7 g/day in patients <65 years. During Part B, dose titrations
288
were permitted only in the patiromer group (and during the first 4 weeks when the
289
primary efficacy endpoint was under evaluation, only if serum potassium was <3.8
290
mEq/L or >5.5 mEq/L). Over the entire phase, patiromer dose increases were reported
291
in 3 (10%) patients ≥65 years and in 5 (19.2%) patients <65 years.
292 293
Safety
294
During Part A and its safety follow-up period, 47% of the patients ≥65 years and 46% of
295
those <65 years reported ≥1 adverse event (Table 2). A total of 10 (7.6%) patients ≥65
296
years and 5 (4.5%) patients <65 years reported an adverse event that led to study
297
discontinuation during the initial treatment phase. Two (1.5%) patients ≥65 years and 1
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(0.9%) patient <65 years reported a total of 6 non-fatal serious adverse events ; none of
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these were considered by the investigator as related to patiromer.
300
The proportions of patients who reported at least 1 adverse event during Part B
301
and its safety follow-up period were generally similar in patients on patiromer vs placebo
302
(Table 3). Two (6.9%) patients ≥65 years who were on patiromer reported constipation;
303
in both, the adverse event was related to patiromer but was not severe or serious. Two
304
(3.3%) patients ≥65 years (1 patiromer, 1 placebo) and none <65 years reported an
305
adverse event that led to study discontinuation during the withdrawal phase. One
306
patient ≥65 years who was on placebo during Part B reported an serious adverse event
307
(mesenteric vessel thrombosis) that led to death; the serious adverse event was
308
reported 36 days after the last dose of patiromer in Part A and was considered by the
309
investigator as not related to patiromer and by the Safety Review Board as not related
310
to hypokalemia or hyperkalemia.
311
Mean serum Mg2+ remained within the normal range during the study. Predefined
312
measures of serum Mg2+ <1.4 mg/dL and serum K+ <3.5 mEq/L (Part A) and <3.8
313
mEq/L (Part B) were infrequent (Tables 2 and 3). In the 8 patients with serum Mg2+
314
<1.4 mg/dL during patiromer treatment, Mg2+ levels increased during follow-up after
315
patiromer was discontinued, regardless of age group. Hypomagnesemia was reported
316
as an adverse event in Part A for 8 patients (5 patients ≥65 years of age and 3 patients
317
<65 year of age; Table 2); and blood Mg2+ decreased was reported as an adverse event
318
in 1 patient <65 years of age. Of note, only 2 (both ≥65 years) of the 9 patients with
319
these adverse events had prespecified serum Mg2+ <1.4 mg/dL (1.3 mg/dL in both
320
patients at or after the adverse events were recorded). All 9 patients received Mg2+
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supplementation and none were discontinued from Part A due to adverse events. In
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Part B, as shown in Table 3, no patients had serum Mg2+ <1.4 mg/dL.
323
Hypomagnesemia was reported as an adverse event in 3 patients (serum Mg2+, 1.7–1.8
324
mg/dL at the time of the event; 2 patients were ≥65 years [1 on patiromer, 1 on placebo]
325
and 1 patient was <65 years and on placebo); and a decrease in blood Mg2+ was
326
reported in 1 patient ≥65 years receiving placebo (serum Mg2+, 1.7 mg/dL at the time of
327
the event). Three of these 4 patients received Mg2+ supplementation and none were
328
discontinued from Part B due to adverse events. No patient had both hypokalemia and
329
hypomagnesemia at any time during the study.
330 331
DISCUSSION
332
This prespecified subgroup analysis of patients aged ≥65 years from the OPAL-HK
333
study shows that patiromer is effective in managing hyperkalemia in patients with
334
chronic kidney disease on RAASi, regardless of age. The effect on lowering serum K+
335
during the initial treatment phase was similar in patients ≥65 years and <65 years, and
336
>96% of all patients achieved normokalemia (serum K+ 3.5–<5.1 mEq/L) at some point
337
during the phase. The magnitude of serum K+ decrease in response to patiromer in
338
patients ≥75 years appears to be consistent with the current findings.38 Of note, more
339
than 50% of patients in each age subgroup were on loop or thiazide diuretics at
340
baseline; however, a previously published analysis of OPAL-HK data showed similar
341
magnitude and time course of reductions in serum K+ in patients on and not on
342
diuretics.45
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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343
Patients aged ≥65 years are more likely to have multiple risk factors for
344
hyperkalemia as a result of age-related comorbidities—such as chronic kidney disease,
345
diabetes, and heart failure—and the use of guideline-recommended RAASi therapy for
346
these conditions.2,3,22,23 Patients in both groups were at similar risk for persistent
347
hyperkalemia as they had similarly low eGFRs, similar proportions of patients in both
348
groups had type 2 diabetes, and all were on RAASi at baseline. The study population
349
represents a real-world population at risk for hyperkalemia who can benefit from RAASi
350
therapy.
351
Our result that the median serum K+ increased in patients—both ≥65 and <65
352
years—who switched to placebo, but not in those who continued patiromer, during the
353
randomized withdrawal phase demonstrates that daily patiromer is needed to maintain
354
normokalemia. Consistent with this, fewer recurrent hyperkalemia events occurred in
355
patients in both age groups who continued patiromer compared with those who
356
switched to placebo. The rate of recurrent hyperkalemia was lower in older vs. younger
357
patients when defined as serum K+ ≥5.1 mEq/L; however, given that there was no
358
difference between age groups in the rate of recurrent hyperkalemia based on serum K+
359
≥5.5 mEq/L, this difference is likely not clinically relevant. As a result of the reduced rate
360
of recurrent hyperkalemia, more patients who continued patiromer in both age groups
361
were able to maintain their RAASi therapy. These exploratory data suggest that
362
patiromer may enable patients with chronic kidney disease, including older patients, to
363
maintain their guideline-recommended RAASi therapy. In the current analysis, more
364
than 50% of patients ≥65 years had heart failure; in a previous report, heart failure
365
patients treated with patiromer in OPAL-HK showed decreases in serum K+ similar to
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
16 Page 16 of 39
366
those seen in the current analysis, with similar proportions of patients achieving
367
normokalemia and remaining on RAASi at study end.42 Hyperkalemia also likely
368
contributes to the cost of managing patients with chronic kidney disease and/or heart
369
failure, both directly (more hospital visits and longer inpatient stays) and indirectly
370
(RAASi discontinuation or dose reduction).25,26,46 The ability of patiromer to lower serum
371
K+ and to prevent recurrent hyperkalemia may also provide economic value.
372
Patiromer was well tolerated in patients regardless of age. During the initial
373
treatment phase, mild-to-moderate gastrointestinal events (eg, constipation, diarrhea,
374
nausea) were the most frequently reported class of adverse events in both subgroups,
375
while the specific events of constipation and diarrhea occurred more frequently in
376
patients ≥65 years. All other adverse events and events leading to study drug
377
discontinuation occurred at similarly low rates in both groups. As described previously,
378
few serious adverse events occurred during the study; none were related to patiromer.43
379
The mean serum Mg2+ levels remained relatively unaltered in patients ≥65 years and
380
<65 years throughout both phases of study and occurrences of serum Mg2+ <1.4 were
381
infrequent and in all cases serum Mg2+ increased during follow-up after patiromer was
382
discontinued. While adverse events of hypomagnesemia or blood Mg2+ decreased
383
occurred in 5 patients ≥65 years and 4 patients <65 years in Part A, only 2 of these
384
patients had serum Mg2+ <1.4 mg/dL at any time during the study. Patients who are at
385
an increased risk for hypomagnesemia (eg, those with diabetes and those treated with
386
loop diuretics or proton pump inhibitors) may warrant closer attention during patiromer
387
treatment. The prescribing information for patiromer recommends that magnesium
388
supplementation be considered for patients who develop low serum Mg2+ levels during
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
17 Page 17 of 39
389
treatment.40 Serum K+ levels <3.8 mEq/L (predefined as hypokalemia in Part A)
390
occurred at low frequency 4% and 2% in patients ≥65 years and <65 years,
391
respectively, and was reversible by patiromer dose adjustment.
392
Finally, as noted previously, patiromer uses calcium as the counter-exchange
393
ion, with approximately 1.6 g of calcium per 8.4 g of patiromer.47 As reported by
394
Bushinsky and colleagues, at the maximal recommended daily dose (25.2 g/day),
395
patiromer administration in healthy adults increased urine calcium by 73 mg/day,
396
suggesting that only a small fraction of the calcium released from patiromer is available
397
for absorption. At the same time, urine phosphate decreased by 64 mg/day, suggesting
398
that some of the released calcium may bind phosphate, which is then excreted in the
399
stool as relatively insoluble salts.48 Nonetheless, clinicians will need to weigh the risk of
400
a potential small increase in calcium absorption compared with the risk of hyperkalemia
401
in patients with chronic kidney disease.
402
Limitations of OPAL-HK have been described previously.43 Briefly, this was a
403
short-term and single-blind study, and the number of patients in the two age groups that
404
received patiromer or placebo during the randomized withdrawal phase was relatively
405
small. However, similar reductions in serum K+ in patients ≥65 years (n=182) and in
406
those <65 years (n=122) were observed in a larger, phase 2 trial of patiromer (personal
407
communication, M. Weir).
408 409
CONCLUSIONS
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
18 Page 18 of 39
410
Treatment with patiromer significantly reduced serum K+ and maintained normokalemia
411
in hyperkalemic patients aged ≥65 years with chronic kidney disease who were on
412
RAASi. As a consequence, significantly more patiromer-treated patients were able to
413
continue guideline-recommended RAASi therapy. Patiromer was well tolerated in
414
patients aged ≥65 years with low rates of discontinuations.
415
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
19 Page 19 of 39
416
ACKNOWLEDGMENTS
417
This study was funded by Relypsa, Inc. Editorial assistance was provided by Narender
418
Dhingra, MBBS, PhD; and was funded by Relypsa, Inc.
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
20 Page 20 of 39
419
References (48 of 40 allowed)
420
1.
worldwide. MMWR Morb Mortal Wkly Rep. 2003;52:101-104,106.
421 422
Centers for Disease Control and Prevention. Trends in aging--United States and
2.
Stevens LA, Viswanathan G, Weiner DE. Chronic kidney disease and end-stage
423
renal disease in the elderly population: current prevalence, future projections,
424
and clinical significance. Adv Chronic Kidney Dis. 2010;17:293-301.
425
3.
failure in elderly persons, 1994-2003. Arch Intern Med. 2008;168:418-424.
426 427
4.
5.
6.
Kemper P, Komisar HL, Alecxih L. Long-term care over an uncertain future: what can current retirees expect? Inquiry. 2005;42:335-350.
432 433
Knickman JR, Snell EK. The 2030 problem: caring for aging baby boomers. Health Serv Res. 2002;37:849-884.
430 431
Tobias DE, Sey M. General and psychotherapeutic medication use in 328 nursing facilities: A year 2000 national survey. Consult Pharm. 2001;16:54-64.
428 429
Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart
7.
Hines AL, Barrett ML, Jiang HJ, et al. Conditions with the largest number of adult
434
hospital readmissions by payer, 2011: Statistical brief #172. Healthcare Cost and
435
Utilization Project (HCUP) Statistical Briefs. Rockville (MD). 2006.
436
8.
failure in elderly persons, 2001-2005. Arch Intern Med. 2008;168:2481-2488.
437 438
Curtis LH, Greiner MA, Hammill BG, et al. Early and long-term outcomes of heart
9.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
439
angiotensin-receptor antagonist irbesartan in patients with nephropathy due to
440
type 2 diabetes. N Engl J Med. 2001;345:851-860.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
21 Page 21 of 39
441
10.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and
442
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N
443
Engl J Med. 2001;345:861-869.
444
11.
Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors
445
and progression of nondiabetic renal disease. A meta-analysis of patient-level
446
data. Ann Intern Med. 2001;135:73-87.
447
12.
Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal
448
outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA.
449
2001;285:2719-2728.
450
13.
Effects of enalapril on mortality in severe congestive heart failure. Results of the
451
Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The
452
CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435.
453
14.
Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on survival in patients with
454
reduced left ventricular ejection fractions and congestive heart failure. The
455
SOLVD Investigators. N Engl J Med. 1991;325:293-302.
456
15.
Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on mortality and the
457
development of heart failure in asymptomatic patients with reduced left
458
ventricular ejection fractions. The SOLVD Investigators. N Engl J Med.
459
1992;327:685-691.
460
16.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting
461
enzyme inhibitors on mortality and morbidity in patients with heart failure.
462
Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450-1456.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
22 Page 22 of 39
463
17.
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality
464
and morbidity in patients with chronic heart failure: the CHARM-Overall
465
programme. Lancet. 2003;362:759-766.
466
18.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity
467
and mortality in patients with severe heart failure. Randomized Aldactone
468
Evaluation Study Investigators. N Engl J Med. 1999;341:709-717.
469
19.
National Kidney Foundation K/DOQI clinical practice guidelines for chronic
470
kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.
471
2002;39:S1-S266.
472
20.
Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO
473
clinical practice guideline for the evaluation and management of CKD. Am J
474
Kidney Dis. 2014;63:713-735.
475
21.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the
476
management of heart failure: executive summary: a report of the American
477
College of Cardiology Foundation/American Heart Association Task Force on
478
practice guidelines. Circulation. 2013;128:1810-1852.
479
22.
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update
480
on New Pharmacological Therapy for Heart Failure: An Update of the 2013
481
ACCF/AHA Guideline for the Management of Heart Failure: A Report of the
482
American College of Cardiology/American Heart Association Task Force on
483
Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll
484
Cardiol. 2016;68:1476-1488.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
23 Page 23 of 39
485
23.
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis
486
and treatment of acute and chronic heart failure: The task force for the diagnosis
487
and treatment of acute and chronic heart failure of the European Society of
488
Cardiology (ESC). Developed with the special contribution of the Heart Failure
489
Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.
490
24.
Diabetes Care. 2017;40:S88-S98.
491 492
American Diabetes Association. 10. Microvascular complications and foot care.
25.
Epstein M, Alvarez PJ, Reaven NL, et al. Evaluation of clinical outcomes and
493
costs based on prescribed dose level of renin-angiotensin-aldosterone system
494
inhibitors. Am J Manag Care 2016;22 (Suppl 11):S313-S326.
495
26.
Ouwerkerk W, Voors AA, Anaker SD, et al. Determinantsand clincical outcome of
496
uptitration of ACE-inhibitors and beta-blockers in patiients with heart failure: a
497
prospective European study. Eur Heart J 2017;
498
http://dx.doi.org/10.1093/eurheartj/ehx026 [Epub ahead of print].
499
27.
angiotensin-aldosterone system. N Engl J Med. 2004;351:585-592.
500 501
28.
29.
Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol. 2010;5:531-548.
504 505
Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med. 1997;12:646-656.
502 503
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-
30.
Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-
506
converting enzyme inhibitors. How much should we worry? Arch Intern Med.
507
1998;158:26-32.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
24 Page 24 of 39
508
31.
significance in chronic kidney disease. Arch Intern Med. 2009;169:1156-1162.
509 510
Einhorn LM, Zhan M, Hsu V, et al. THe frequency of hyperkalemia and its
32.
Berkova M, Berka Z, Topinkova E. Arrhythmias and ECG changes in life
511
threatening hyperkalemia in older patients treated by potassium sparing drugs.
512
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;158:84-91.
513
33.
Genovesi S, Valsecchi MG, Rossi E, et al. Sudden death and associated factors
514
in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant.
515
2009;24:2529-2536.
516
34.
Miao Y, Dobre D, Heerspink HJ, et al. Increased serum potassium affects renal
517
outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the
518
Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia. 2011;54:44-50.
519
35.
Epstein M, Pitt B. Recent advances in pharmacological treatments of
520
hyperkalemia: focus on patiromer. Expert Opin Pharmacother. 2016;17:1435-
521
1448.
522
36.
Epstein M, Reaven NL, Funk SE, et al. Evaluation of the treatment gap between
523
clinical guidelines and the utilization of renin-angiotensin-aldosterone system
524
inhibitors. Am J Manag Care. 2015;21:S212-S220.
525
37.
current data and opportunities for the future. Hypertension. 2015;66:731-738.
526 527
38.
530
Kumar R, Kanev L, Woods SD, et al. Managing hyperkalemia in high-risk patients in long-term care. Am J Manag Care Supplement. 2017;23:S27-S36.
528 529
Pitt B, Bakris GL. New potassium binders for the treatment of hyperkalemia:
39.
Li L, Harrison SD, Cope MJ, et al. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross-linked polymer that lowers serum potassium
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
25 Page 25 of 39
531
concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther.
532
2016;21:456-465.
533
40.
Veltassa (patiromer) for oral suspension [package insert]: Relypsa, Inc.; 2016.
534
41.
European Medicines Agency. Veltassa.
535
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicine
536
s/004180/human_med_002141.jsp&mid=WC0b01ac058001d124. Accessed
537
August 15, 2017.
538
42.
Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum
539
potassium and preventing recurrent hyperkalaemia in patients with heart failure
540
and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail. 2015;17:1057-
541
1065.
542
43.
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney
543
disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med.
544
2015;372:211-221.
545
44.
Bakris GL, Pitt B, Weir MR, et al. Effect of patiromer on serum potassium level in
546
patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN
547
randomized clinical trial. JAMA. 2015;314:151-161.
548
45.
Weir MR, Mayo MR, Garza D, et al. Effectiveness of patiromer in the treatment of
549
hyperkalemia in chronic kidney disease patients with hypertension on diuretics. J
550
Hypertens. 2017;35(suppl 1):S57-S63.
551 552
46.
Polson M, Evangelatos T, Lord T, et al. Clinical and economic impact of hyperkalemia in patients with chronic kidney disease and heart failure (abstract).
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
26 Page 26 of 39
553
Academy of Managed Care Pharmacy Nexus. Vol 22. National Harbor, Maryland:
554
J Manag Care Spec Pharm; 2016:S43.
555
47.
2016;4:237.
556 557 558
Bakris G, Weir M, Epstein M. Letter to the Editor. J Cardiovasc Dis Diagn.
48.
Bushinsky DA, Spiegel DM, Gross C, et al. Effect of patiromer on urinary ion excretion in healthy adults. Clin J Am Soc Nephrol. 2016;11:1769-1776.
559 560 561 562
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Figures
564 565
Figure 1 Effect of patiromer on serum K+ in patients aged ≥65 and <65 years during the
566
initial treatment phase (Part A). Estimates of mean (SE) serum K+ by visit
567
were based on models that included presence or absence of heart failure and
568
presence or absence of type 2 diabetes. The post-baseline models also
569
included the baseline serum K+ value. Baseline and day 3 means were
570
estimated using ANOVA models; estimates at weeks 1–4 were based on
571
mixed models with repeated measures. ANOVA, analysis of variance; K +,
572
potassium; SE, standard error.
573
[Please print the Figure in color at either 1.5- or double-column width]
574 575
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28 Page 28 of 39
576 577
Figure 2 Proportion of patients with recurrent hyperkalemia (panel A, ≥5.5 mEq/L; panel
578
B ≥5.1 mEq/L) at any time through 8 weeks of the randomized withdrawal
579
phase (Part B). HK, hyperkalemia; K+, potassium.
580
[Please print the Figure in color at single-column width]
581 582
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
29 Page 29 of 39
583 584
Figure 3 Proportion of patients who required management of recurrent hyperkalemia
585
and who remained on RAASi at the end of the randomized withdrawal phase
586
(Part B). *The protocol required different interventions for the management of
587
recurrent hyperkalemia (ie, RAASi dose reduction or discontinuation in the
588
placebo group and patiromer dose increase or RAASi discontinuation in the
589
patiromer group). †Could be at the final visit (week 8), or earlier if the patient
590
discontinued. HK, hyperkalemia; K+, potassium; RAASi, renin-angiotensin-
591
aldosterone-system inhibitors.
592
[Please print the Figure in color at single-column width]
593
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
30 Page 30 of 39
594 595
Figure 4 Time to RAASi discontinuation during the randomized withdrawal phase (Part
596
B). Circles indicate censored observations. RAASi, renin-angiotensin-
597
aldosterone-system inhibitors.
598
[Please print the Figure in color at either 1.5- or double-column width]
599 600
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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601 602
Table 1 Baseline Demographic and Clinical Characteristics at Baseline in the Initial Treatment Phase (Part A) by Age Group Parameter
603 604 605 606 607 608 609 610 611
≥65 years (n = 131) 76 (58.0) 71.7 (4.4)
<65 years (n = 112) 64 (57.1) 55.5 (8.6)
Male, n (%) Age (years), mean (SD) <65 years 65-69 years 70-74 years ≥75 years White, n (%) Chronic kidney disease stage (eGFR in mL/min/1.73 m2), n (%)* Stage 2† (60–<90) Stage 3A (45–<60) Stage 3B (30–<45) Stage 4/5 (<30) Type 2 diabetes mellitus, n (%) Heart failure, n (%) Time since diagnosis (years), mean (SD) Myocardial infarction, n (%) Hypertension, n (%) eGFR (mL/min/1.73 m2), mean (SD)
12 (9.2) 32 (24.4) 31 (23.7) 56 (42.7)
10 (8.9) 17 (15.2) 32 (28.6) 53 (47.3)
78 (59.5) 68 (51.9) 4.0 (5.0) 34 (26.0) 127 (96.9) 36.8 (16.1)‡
61 (54.5) 34 (30.4) 2.7 (3.2) 26 (23.2) 109 (97.3) 33.9 (16.3)‡
Serum blood urea nitrogen (mg/dL), mean (SD) Serum creatinine (mg/dL), mean (SD) Serum K+ (mEq/L), mean (SD)§ n
37.0 (17.0) 1.92 (0.8)¶ 5.59 (0.54) 130
41.8 (19.1) 2.34 (1.2)¶ 5.56 (0.49) 108
129 (98.5)
46.1% 18.5% 18.5% 16.8%
110 (98.2)
*Classification of chronic kidney disease stage at baseline was determined by central laboratory eGFR values. None of the patients had stage 1 chronic kidney disease. † Approximately 9% of patients in each subgroup who met the entry criteria based on their local laboratory eGFR values were reclassified on the basis of their central eGFR values as having stage 2 chronic kidney disease at baseline. ‡P = NS and ¶P <0.01 for difference between age groups (one-way ANOVA). §By central laboratory measurements. ANOVA, analysis of variance; eGFR, estimated glomerular filtration rate; K+, potassium; SD, standard deviation.
612
32 Page 32 of 39
613 614
Table 2 Adverse Events During Initial Treatment Phase (Part A) and Its Safety Followup by Age Group ≥65 years (n = 131) 62 (47.3)
<65 years (n = 112) 52 (46.4)
19 (14.5) 7 (5.3) 5 (3.8) 5 (3.8) 4 (3.1) 2 (1.5) 4 (3.1) 2 (1.5) 0 (0)
7 (6.3) 1 (0.9) 3 (2.7) 3 (2.7) 3 (2.7) 5 (4.5) 2 (1.8) 4 (3.6) 4 (3.6)
36 (27.5) 17 (13) 6 (4.6) 5 (3.8)
17 (15.2) 7 (6.3) 1 (0.9) 2 (1.8)
1 (0.8) 2 (1.5)
0 (0) 1 (0.9)
5 (4.0)
2 (1.8)
<1.4 mg/dL
5 (4.0)
3 (2.7)
<1.2 mg/dL
0
0
Adverse Event, n (%)* At least 1 adverse event Most common adverse events† Constipation Diarrhea Hypomagnesemia Nausea Anemia Worsening of chronic kidney disease Hyperkalemia Left ventricular hypertrophy Reduced GFR Most common patiromer-related adverse events† Any patiromer-related adverse event Constipation Diarrhea Hypomagnesemia Other adverse events of interest Edema (peripheral) At least 1 serious adverse event Prespecified electrolytes of interest‡ Serum K+ <3.5 mEq/L Serum Mg2+
615 616 617 618 619
*Based on Safety Population. †Occurring in >3% of patients in either subgroup; presented by descending number of patients for both subgroups combined. ‡Available for 126 patients ≥65 years and 111 patients <65 years. GFR, glomerular filtration rate; K+, potassium; Mg2+, magnesium.
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
33 Page 33 of 39
620 621 622
Table 3 Adverse Events During Withdrawal Phase (Part B) and Its Safety Follow-up by Age Group <65 years
≥65 years Patiromer (n = 29)
Placebo (n = 31)
Patiromer (n = 26)
Placebo (n = 21)
15 (51.7)
17 (54.8)
11 (42.3)
9 (42.9)
Constipation
2 (6.9)
0
0
0
Nausea
2 (6.9)
0
0
0
Headache
1 (3.4)
2 (6.5)
1 (3.8)
2 (9.5)
Influenza
1 (3.4)
1 (3.2)
0
2 (9.5)
Hyperkalemia
0
2 (6.5)
1 (3.8)
0
Hepatic enzyme increased
0
2 (6.5)
1 (3.8)
0
Hypertension
0
0
0
3 (14.3)
4 (13.8)
2 (6.5)
0
0
2 (6.9)
0
0
0
0 0
0 1 (3.2)
0 0
0 0
2 (6.9)
1 (3.2)
1 (3.9)
0
0 0
0 0
0 0
0 0
Adverse Event, n (%)* At least 1 adverse event Most common adverse events†
Most common patiromer-related adverse events Any patiromer-related adverse event Constipation Adverse events of interest Edema (peripheral) At least 1 serious adverse event Prespecified electrolytes of interest Serum K+ <3.8 mEq/L‡ Serum Mg2+ <1.4 mg/dL <1.2 mg/dL 623 624 625 626 627 628
†
*Based on Safety Population. †Occurring in ≥2 patients in any subgroup; presented in descending order of incidence in patients ≥65 on patiromer. ‡During the withdrawal phase and its follow-up period, hypokalemia was predefined as serum K + <3.8 mEq/L, the protocol-specified criterion for study withdrawal. K+, potassium; Mg2+, magnesium.
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
34 Page 34 of 39
629
Supplementary Appendix
630
This appendix has been provided by the authors to give readers additional information
631
about their work.
632
Supplement to: Weir MR, Bushinsky DA, Benton WW, et al. Effect of Patiromer on
633
Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients on Renin-
634
Angiotensin-Aldosterone-System Inhibitors
635 636 637 638
Table of Contents Supplementary Figure 1 Change in serum K+ from baseline to week 4 of the randomized withdrawal phase (Part B) by age group. ................................................... 36
639 640 641
Supplementary Figure 2 Kaplan-Meier estimates of the time to time to first serum potassium level ≥5.5 mEq/L (Panels A and B) and ≥5.1 mEq/L (Panels C and D) by age subgroup. ...................................................................................................................... 37
642 643
Supplementary Table 1 Concomitant Medications at Baseline in the Initial Treatment Phase (Part A) by Age Group........................................................................................ 38
644
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
35 Page 35 of 39
645
Supplementary Figure 1 Change in serum K+ from baseline to week 4 of the
646
randomized withdrawal phase (Part B) by age group.
647
*For comparison between treatment groups in mean rank change. K+, potassium.
648 649
36 Page 36 of 39
650 651
Supplementary Figure 2 Time to first serum potassium level ≥5.5 mEq/L (Panels A and B) and ≥5.1 mEq/L (Panels C and D) by age subgroup.
652
653
654 655
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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656
657 658
Supplementary Table 1 Concomitant Medications at Baseline in the Initial Treatment Phase (Part A) by Age Group. ≥65 years <65 years Moderate/ Moderate/ Concomitant Total Mild HK Severe Mild HK Severe Total Medication (n = (n = 53) HK (n = 39) HK (n = 112) 131) (n = 78) (n = 73) Number of 6.8 medications, mean 6.6 (2.9) 6.7 (2.9) 6.1 (3.5) 5.6 (2.9) 5.8 (3.1) (2.9) (SD) 53 131 (100) (100) RAASi medication, n 39 (100) 38 90 (%) 30 112 (71.7) 78 (100) (68.7) 73 (100) ACE inhibitor (76.9) (100) 19 52 (66.7) 48 50 (68.5) ARB 14 80 (71.4) (35.8) 29 (37.2) (36.6) 30 (41.1) Aldosterone (35.9) 44 (39.3) 10 7 (9.0) 17 4 (5.5) antagonist 1 (2.6) 5 (4.5) (18.9) 0 (13.0) 1 (1.4) Renin inhibitor 0 1 (0.9) 1 (1.9) 10 (12.8) 1 (0.8) 12 (16.4) * Dual RAASi 6 (15.4) 18 (16.1) 13 37 (47.4) 23 27 (37.0) On maximal RAASi 15 42 (37.5) (24.5) (17.6) † dose (38.5) 27 64 (50.9) (48.9) Non-RAASi, nondiuretic antihypertensives, n (%) Beta blocker Calcium channel blocker Alpha blocker
40 (75.5) 30 (56.6) 18 (34.0) 8 (15.1)
Non-RAASi diuretics, n (%) Thiazide or thiazidelike Loop Insulin, n (%) Long-acting Intermediate-acting Short-acting Combination +
28 (52.8) 12 (22.6) 18 (34.0) 12 (22.6) 4 (7.5) 2 (3.8) 6 (11.3)
67 (85.9) 45 (57.7) 43 (55.1) 8 (10.3)
41 (52.6) 21 (26.9) 26 (33.3) 11 (14.1) 6 (7.7) 2 (2.6) 3 (3.8) 3 (3.8)
107 (81.7) 75 (57.3) 61 (46.6) 16 (12.2) 69 (52.7) 33 (25.2) 44 (33.6) 23 (17.6) 10 (7.6) 4 (3.1) 9 (6.9)
23 (59.0) 16 (41.0) 19 (48.7) 2 (5.1) 22 (56.4) 13 (33.3) 11 (28.2) 8 (20.5) 4 (10.3) 1 (2.6) 6 (15.4) 0 (0)
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
56 (76.7) 37 (50.7) 32 (43.8) 4 (5.5)
79 (70.5) 53 (47.3) 51 (45.5) 6 (5.4)
41 (56.2) 24 (32.9) 22 (30.1)
63 (56.3) 37 (33.0) 33 (29.5)
24 (32.9) 8 (11.0) 8 (11.0) 20 (27.4) 2 (2.7)
32 (28.6) 12 (10.7) 9 (8.0) 26 (23.2) 2 (1.8) 38 Page 38 of 39
Non-insulin antidiabetic, n (%) Biguanides Sulfonylureas Others Magnesium supplementation, n (%) Warfarin, n (%)
4 (7.5)
7 (5.3)
23 (43.4) 10 (18.9) 15 (28.3) 3 (5.7)
33 (42.3) 14 (17.9) 25 (32.1) 3 (3.8)
56 (42.7) 24 (18.3) 40 (30.5) 6 (4.6)
11 (28.2) 4 (10.3) 7 (17.9) 3 (7.7)
19 (26.0) 6 (8.2) 17 (23.3) 0
30 (26.8) 10 (8.9) 24 (21.4) 3 (2.7)
5 (9.4)
8 (10.3)
13 (9.9)
3 (7.7)
8 (11.0)
11 (9.8)
5 (9.4)
8 (10.3)
13 (9.9)
3 (7.7)
0
3 (2.7)
659 660
*Any combination of two or more of the following: ACE inhibitor, ARB, aldosterone
661
antagonist, and renin inhibitor. †As assessed by the investigator in accordance with
662
local standards of care. ACE, angiotensin-converting enzyme; ARB, angiotensin II
663
receptor blocker; HK, hyperkalemia; RAASi, renin-angiotensin-aldosterone system
664
inhibitors; SD, standard deviation.
665
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S0002-9343(17)31203-2 https://doi.org/10.1016/j.amjmed.2017.11.011 AJM 14394
To appear in:
The American Journal of Medicine
Please cite this article as: Matthew R. Weir, David A. Bushinsky, Wade W. Benton, Steven D. Woods, Martha R. Mayo, Susan P. Arthur, Bertram Pitt, George L. Bakris, Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients on Renin-AngiotensinAldosterone-System Inhibitors, The American Journal of Medicine (2017), https://doi.org/10.1016/j.amjmed.2017.11.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease
2
Patients on Renin-Angiotensin-Aldosterone-System Inhibitors
3
Matthew R. Weir, MD;a David A. Bushinsky, MD;b Wade W. Benton, PharmD;c Steven
4
D. Woods, PharmD;c Martha R. Mayo, PharmD;c Susan P. Arthur, PhD;c Bertram Pitt,
5
MD;d George L. Bakris, MDe
6 7
a
Division of Nephrology, Department of Medicine, University of Maryland School of
8
Medicine, 22 S. Greene St., Room N3W143, Baltimore, MD, USA, 21201;
9
[email protected];
10
b
Division of Nephrology, Department of Medicine, University of Rochester School of
11
Medicine, 601 Elmwood Ave., Box 675, Rochester, NY, USA, 14642;
12
[email protected];
13
c
Relypsa, Inc., a Vifor Pharma Group Company, 100 Cardinal Way, Redwood City, CA,
14
USA, 94063; [email protected]; [email protected]; [email protected];
15
[email protected];
16 17 18 19
d
Department of Internal Medicine, University of Michigan School of Medicine, 1500 East
Medical Center Drive, Ann Arbor, MI, USA, 48109; [email protected]; e
Comprehensive Hypertension Center, Department of Medicine, University of Chicago
Medicine, 5841 S Maryland Ave, Chicago, IL, USA, 60637; [email protected];
20 21 22 23 24 25 26 27 28 29 30 31 32
Corresponding Author: Matthew R. Weir, MD Professor and Director Division of Nephrology University of Maryland School of Medicine 22 S. Greene St., Room N3W143 Baltimore, MD 21201 USA Tel: +1 410-328-5720 Fax +1 410-328-5685 Email: [email protected]
33
Funding: This study was funded by Relypsa, Inc., a Vifor Pharma Group Company 1 Page 1 of 39
34
Conflict-of-Interest Statement: Dr. Weir reports personal fees for scientific advisory
35
boards from Relypsa, Inc. and Vifor Pharma Management Ltd., both Vifor Pharma
36
Group Companies; and from ZS Pharma, Akebia, Janssen, AstraZeneca, Sanofi, MSD,
37
AbbVie, and Boston Scientific outside the submitted work. Dr. Bushinsky reports
38
personal fees from and past stock ownership of Relypsa, Inc., a Vifor Pharma Group
39
Company; personal fees outside the submitted work from Amgen, Sanofi/Genzyme,
40
OPKO, and Tricida; and stock outside of the submitted work in Amgen and Tricida. He
41
reports research support from the National Institutes of Health and from the Renal
42
Research Institute outside of the submitted work. Drs. Mayo, Woods, and Arthur
43
report employment by and past stock ownership of Relypsa, Inc., a Vifor Pharma Group
44
Company. Dr. Benton reports employment by Relypsa, Inc., a Vifor Pharma Group
45
Company, when the study was conducted. Dr. Pitt reports personal fees for consulting
46
with Sanofi, Relypsa, Inc., a Vifor Pharma Group Company, Merck, Bayer,
47
AstraZeneca, Boehringer Ingelheim, Forest Laboratories, scPharmaceuticals,
48
PharMain, Tricida, DaVinci Therapeutics, KBP Biosciences, Stealth Peptides, and
49
AuraSense. He has stock options with scPharmaceuticals, PharMain, DaVinci
50
Therapeutics, Tricida, KBP Biosciences, and AuraSense. He serves on a data safety
51
monitoring committee for and receives personal fees from Johnson & Johnson,
52
Novartis, and Tenax Pharmaceuticals. He serves on a clinical events committee and
53
receives personal fees from Juventas Therapeutics. In addition, he has a pending
54
patent EFS ID 14916043, application number 61762661/UM-33001/US-1PRO, for the
55
site-specific delivery of eplerenone to the myocardium. Dr. Bakris reports personal fees
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
2 Page 2 of 39
56
and other from Relypsa, Inc., a Vifor Pharma Group Company; grants from AbbVie,
57
Janssen, and Bayer.
58 59
All authors had access to the data and a role in writing the manuscript.
60 61
Journal: American Journal of Medicine (type: Clinical Research Study)
62
Key Words: Chronic kidney disease; RAASi; Patiromer; Aging
63
Running Head: Patiromer Lowers Serum K+ in Older Chronic Kidney Disease Patients
64 65
Number of Words (Abstract): 266 of 250 allowed
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Number of Words (Total): 3381 of 3000 allowed (including text, and acknowledgement
67
but NOT including abstract, tables, references, clinical significance, or title page)
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CLINICAL SIGNIFICANCE (69 words of 70 allowed)
predisposed to risk of hyperkalemia.
72 73
Because of age, comorbidity, and polypharmacy, older patients are particularly
Patiromer significantly decreased serum K+ in hyperkalemic patients aged ≥65
74
years with chronic kidney disease on RAASi and reduced the risk of recurrent
75
hyperkalemia.
76
RAASi medications compared with those on placebo.
77 78
A significantly larger proportion of patients on patiromer continued to receive
Patiromer was well tolerated in patients aged ≥65 years and <65 years.
79 80
ABSTRACT (266 of 250 allowed)
81
Background: Older people are predisposed to hyperkalemia because of impaired renal
82
function, comorbid conditions, and polypharmacy. Renin-angiotensin-aldosterone
83
system inhibitors (RAASi), guideline-recommended for the treatment of chronic kidney
84
disease and heart failure, further augment the risk. Patiromer, a nonabsorbed
85
potassium binder, was shown in a phase 3 study (OPAL-HK) to decrease serum
86
potassium in patients with chronic kidney disease on RAASi. We studied the efficacy
87
and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from
88
OPAL-HK.
89
Methods: Chronic kidney disease patients with mild or moderate-to-severe
90
hyperkalemia received patiromer, initially 8.4 g/day or 16.8 g/day, respectively, for 4
91
weeks (treatment phase, Part A). Eligible patients entered an 8-week randomized
92
withdrawal phase (Part B) and either continued patiromer or switched to placebo.
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93
Results: The mean ± standard error change in serum potassium from baseline to week
94
4 of Part A (primary endpoint) in patients ≥65 years was −1.01 ± 0.05 mEq/L (P <0.001);
95
97% achieved normokalemia (serum potassium 3.8–<5.1 mEq/L). The increase in
96
serum potassium during the first 4 weeks of Part B was significantly greater in patients
97
on placebo than in those on patiromer (P <0.001). Significantly fewer patients on
98
patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum
99
potassium ≥5.1 mEq/L). The most common adverse event in patients ≥65 years was
100
mild-to-moderate constipation (15% in Part A, 7% in Part B). Serum potassium <3.5
101
mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients ≥65
102
years in Part A).
103
Conclusions: Patiromer reduced serum potassium and recurrent hyperkalemia, and
104 105
was well tolerated in older patients with chronic kidney disease on RAASi. INTRODUCTION
106
The number of US adults aged ≥65 years is expected to increase from 420 million in
107
2000 to 973 million (12.0%) in 2030.1 Advancing age is associated with increased
108
prevalence of chronic conditions such as chronic kidney disease, heart failure,
109
hypertension, and diabetes.2,3 Together, aging and chronic conditions contribute to
110
increased hospitalizations, medical interventions, and use of long-term care services,
111
thereby significantly increasing the economic burden on the healthcare system.4–8 In several clinical studies, use of renin-angiotensin-aldosterone system inhibitors
112 113
(RAASi) has been shown to slow the progression of diabetic and nondiabetic chronic
114
kidney disease9–12 and to reduce morbidity and mortality in patients with heart failure.13–
115 116
18
American and European guidelines recommend RAASi for the treatment of these
conditions.19–24 RAASi prescribed at the maximum recommended dose, compared with
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117
submaximal doses, may improve clinical outcomes and reduce total costs.25,26 However,
118
RAASi use increases hyperkalemia risk, especially in older patients with reduced
119
aldosterone production, reduced glomerular filtration rate (GFR), and impaired renal
120
tubular function.27–31
121
Hyperkalemia can lead to life-threatening aberrations in cardiac conduction,
122
arrhythmias, and sudden death.28,31,32 RAASi-induced hyperkalemia is associated with
123
increased risk of adverse renal outcomes and mortality in patients with chronic kidney
124
disease.31,33,34 Physicians may discontinue or reduce the RAASi dose, or they may not
125
initiate RAASi, due to hyperkalemia concerns.35 Retrospective analysis of medical
126
records of patients with chronic kidney disease, heart failure, or diabetes suggests that
127
maximum doses of RAASi are either discontinued or dose-reduced almost 50% of the
128
time following a moderate-to-severe hyperkalemic event.36 Lowering serum potassium
129
(K+) levels in hyperkalemic patients on RAASi may improve clinical outcomes by
130
prevention of hyperkalemia-associated cardiac adverse effects and allowing
131
continuation of guideline-recommended RAASi therapy.37,38
132
Patiromer (Veltassa®; Relypsa, Inc., a Vifor Pharma Group Company, Redwood
133
City, CA), a nonabsorbed, sodium-free K+-binder that acts predominantly in the colon
134
and uses calcium as the counter-exchange ion,39 is approved in the US and the EU for
135
the treatment of hyperkalemia.40,41 Patiromer has been demonstrated to be effective in
136
lowering serum K+ levels and generally safe in hyperkalemic patients with chronic
137
kidney disease on RAASi, many of whom also had heart failure, diabetes, and/or
138
hypertension.37,42–44 In the phase 3 OPAL-HK trial, patiromer significantly decreased the
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139
rate of recurrent hyperkalemia.43 Here, we studied the efficacy and safety of patiromer
140
in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.
141 142
METHODS
143
Study Design and Patient Population
144
The OPAL-HK study has been described previously.43 Briefly, 243 patients were
145
enrolled in a 4-week initial treatment phase (Part A). Eligible patients were adults (18–
146
80 years old) with chronic kidney disease stage 3 or 4 (estimated GFR [eGFR] 15–<60
147
mL/min/1.73 m2) and hyperkalemia (serum K+ 5.1–<6.5 mEq/L by local laboratory
148
measurement) who were on a stable dose of ≥1 RAASi medications for ≥28 days at
149
screening.
150
At the beginning of Part A, patients with mild hyperkalemia (serum K+ 5.1–<5.5
151
mEq/L) at screening were assigned to patiromer 8.4 g/day; those with moderate-to-
152
severe hyperkalemia (5.5–<6.5 mEq/L) were assigned to patiromer 16.8 g/day (all
153
doses were given BID). The patiromer dose was adjusted according to a prespecified
154
titration algorithm to maintain serum K+ within the range of 3.8–<5.1 mEq/L. During this
155
phase, RAASi therapy was not allowed to be adjusted unless medically necessary but
156
could be discontinued if serum K+ was ≥6.5 mEq/L (or ≥5.1 mEq/L for patients on
157
maximum patiromer dose).
158
Patients who had serum K+ ≥5.5 mEq/L at baseline of Part A and were
159
normokalemic (serum K+ 3.8–<5.1 mEq/L), while receiving patiromer and on ≥1 RAASi
160
medications at the end of Part A, were eligible to enter Part B (8-week placebo-
161
controlled randomized withdrawal phase). Patients meeting these criteria (n = 107) were
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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162
randomized 1:1 to continue patiromer at the daily dose they were receiving at week 4 of
163
Part A or to switch to placebo. Recurrence of hyperkalemia (serum K+ ≥5.5 mEq/L)
164
during Part B was managed with a prespecified algorithm as described previously.43
165
Laboratory assessments, conducted at baseline (day 1), day 3 of each phase,
166
and weekly thereafter, included serum K+ and serum chemistry (including creatinine and
167
eGFR). Sitting blood pressure was measured in triplicate at each visit.
168 169
Efficacy and Safety Assessments
170
Analysis of the primary efficacy endpoints for Part A and Part B were prespecified by
171
age (≥65 years, <65 years): Part A, change in serum K+ from baseline to week 4 of the
172
initial treatment phase; Part B, between group difference in change in serum K+ from
173
start to week 4 of the randomized withdrawal phase. During the first 4 weeks of Part B,
174
changes in patiromer or RAASi doses were not permitted unless serum K + was ≥5.5
175
mEq/L in order to facilitate interpretation of the primary endpoint (see the online
176
supplement to Weir et al43 for details). Analysis of the secondary efficacy endpoint in
177
Part B was prespecified by age group: proportion of patients with serum K+ ≥5.5 mEq/L
178
and serum K+ ≥5.1 mEq/L at any time during Part B.43
179
Other efficacy endpoints were assessed post-hoc by age group, including: Part
180
A, proportion of patients with serum K+ in the normal range (3.8–<5.1 mEq/L) at any
181
time; and Part B, time to recurrent hyperkalemia; time to RAASi discontinuation;
182
proportion of patients requiring intervention to manage hyperkalemia (defined as
183
patiromer dose increase or RAASi discontinuation for patients on patiromer and RAASi
184
dose decrease of ≥50% or RAASi discontinuation for patients on placebo); and
185
proportion of patients on RAASi at the end of the withdrawal phase. +
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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186
Safety was evaluated in each age group by adverse events, change in blood
187
pressure, change in serum magnesium (Mg2+), and proportions of patients with serum
188
Mg2+ <1.4 mg/dL or serum K+ <3.5 mEq/L.
189 190
Statistical Analyses
191
Initial treatment phase (Part A)
192
Mean change in serum K+ from baseline to week 4 was assessed in enrolled patients
193
who received ≥1 dose of patiromer and had ≥1 post-baseline weekly serum K+
194
measurement. The mean changes in serum K+ (± standard error [SE]) and 95%
195
confidence intervals (CIs) were estimated separately by age group using longitudinal
196
repeated-measures models that included presence or absence of heart failure,
197
presence or absence of type 2 diabetes, and baseline serum K+.
198 199
Randomized withdrawal phase (Part B)
200
Change in serum K+ at week 4 or first local serum K+ <3.8 or ≥5.5 mEq/L was compared
201
between treatment groups, separately for each age group, using ranked values of
202
change in serum K+ and an analysis of variance (ANOVA) model that included
203
treatment group, level of serum K+ at the start of the initial treatment phase (<5.8 mEq/L
204
or ≥5.8 mEq/L), and presence or absence of type 2 diabetes. The difference and 95%
205
CI between the treatment groups in median change from baseline were estimated,
206
within age group, using a Hodges-Lehmann estimator.
207
Proportions of subjects with recurrent hyperkalemia (serum K+ ≥5.5 mEq/L and
208
≥5.1 mEq/L) at any time during the withdrawal phase were stratified by serum K + level
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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209
at the start of the initial phase of the study (<5.8 mEq/L or ≥5.8 mEq/L) and by presence
210
or absence of type 2 diabetes. Treatment groups were compared, separately by age
211
group, using the Mantel-Haenszel test.
212
Kaplan-Meier methods were used to estimate the time to recurrent hyperkalemia
213
and time to discontinuation of RAASi during the withdrawal phase. Additional details
214
regarding statistical methods were published previously.43
215 216
RESULTS
217
Patient Disposition
218
Of patients enrolled in Part A, 131 (54%) were aged ≥65 years and 112 (46%) <65
219
years; 87% and 94%, respectively, completed Part A. The two most common reasons
220
for discontinuation were adverse events (7 [5%] ≥65 years and 3 [3%] <65 years) and
221
consent withdrawal (4 [3%] and 1 [1%], respectively).
222
Of 107 patients who met eligibility criteria to enter Part B, 60 (56%) were ≥65
223
years and 47 (44%) were <65 years. Among patients who completed Part A, the most
224
common reason for ineligibility for Part B was serum K+ level <5.5 mEq/L at baseline of
225
Part A (48 [42%] ≥65 years and 49 [47%] <65 years). A total of 40 (67%) patients ≥65
226
years (22/29 [76%] on patiromer and 18/31 [58%] on placebo) and 35 (74%) patients
227
<65 years (23/26 [88%] on patiromer and 12/21 [57%] on placebo) completed the study.
228
The most common reason for discontinuation was high serum K+ level meeting protocol-
229
specified withdrawal criterion, occurring in 2 patients (4%) on patiromer and 14 (27%)
230
on placebo.
231
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232
Baseline Demographic and Clinical Characteristics in Part A
233
Mean (standard deviation [SD]) age was 71.7 (4.4) years for patients ≥65 years, and
234
55.5 (8.6) years for those <65 years (Table 1). Approximately 24% of patients ≥65 years
235
and 29% <65 years had stage 3B chronic kidney disease; 43% and 47%, respectively,
236
had stage 4/5 chronic kidney disease (Table 1). There was no difference in mean (SD)
237
eGFR between the two subgroups, whereas serum creatinine was lower in patients ≥65
238
years (P <0.01; Table 1). Heart failure was presentin 52% of patients ≥65 years and in
239
30% of those <65 years. The mean (SD) serum K+ was similar by age group (≥65 years:
240
5.59 [0.54] mEq/L, <65 years: 5.56 [0.49] mEq/L). Patients ≥65 years were taking 6.7
241
concomitant medications on average at baseline, and those <65 years were taking 5.8;
242
all were on RAASi medications (primarily ACE inhibitors) and a majority were taking
243
non-RAASi, nondiuretic antihypertensives and non-RAASi diuretics. (Supplementary
244
Table 1).
245 246
Efficacy
247
Initial treatment phase (Part A)
248
The estimated mean ± SE change in serum K+ from baseline to week 4 in patients who
249
received ≥1 dose of patiromer and had ≥1 serum K+ measurement after day 3 was
250
−1.01 ± 0.05 mEq/L (95% CI, −1.10, −0.92) for patients ≥65 years (n = 126) and −0.96 ±
251
0.05 mEq/L (−1.05, −0.88) for those <65 years (n = 111; P <0.001 for both); P=0.50 for
252
difference between age groups. The estimated mean ± SE serum K+ for patients ≥65
253
years and <65 years during Part A is shown in Figure 1.
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
11 Page 11 of 39
254
Among patients with ≥1 centrally measured serum K+ value after baseline, the
255
proportion that achieved normokalemia (serum K+ 3.8–<5.1 mEq/L) at any time during
256
Part A was 97%, both for patients ≥65 years (122/126) and for those <65 years
257
(108/111).
258
The mean daily dose of patiromer during Part A was 17.5 g in patients ≥65 years
259
and 19.0 g in patients <65 years. Of the 78/131 patients ≥65 years and the 69/112
260
patients <65 years who required a dose adjustment, the majority (53 [68%] and 38
261
[55%], respectively) required only one adjustment.
262 263
Randomized withdrawal phase (Part B)
264
Mean (SD) serum K+ for patients ≥65 years who entered Part B was 4.51 (0.42) mEq/L.
265
During the first 4 weeks of this phase, serum K+ levels remained stable in patiromer-
266
treated patients and increased in placebo-treated patients. Differences between the
267
patiromer vs placebo groups in the median (95% CI) change in serum K+ were 0.81
268
(0.49, 1.14) mEq/L (P <0.001) in patients ≥65 years and 0.57 (0.11, 1.03) mEq/L (P =
269
0.006) in patients <65 years (Supplementary Figure 1).
270
Among patients aged ≥65 years on patiromer vs placebo, 11% vs 64% (P
271
<0.001) had at least one serum K+ value ≥5.5 mEq/L and 30% vs 92% (P <0.001) had
272
at least one serum K+ value ≥5.1 mEq/L (Figure 2). Results for patients <65 years were
273
generally similar, although the difference between treatment groups in the proportion
274
with serum K+ ≥5.1 mEq/L was more pronounced in the older vs the younger age group
275
(P <0.05) (Figure 2). The time to first recurrence of hyperkalemia is shown in
+
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276
Supplementary Figure 2 (Panels A and B, time to first serum K+ level >5.5 mEq/L;
277
Panels C and D, time to first serum K+ level >5.1 mEq/L).
278
The proportion of patients ≥65 years who required an intervention to manage
279
hyperkalemia was 10% for patiromer vs 71% for placebo (Figure 3A). All patients ≥65
280
years (100%) receiving patiromer, compared with 48% of those on placebo, continued
281
to be on RAASi at the end of Part B (Figure 3B). Results for patients <65 years were
282
similar (Figure 3). Time to RAASi discontinuation is shown in Figure 4.
283
During Part A, mean daily patiromer doses were similar in patients subsequently
284
randomized to continue patiromer (18.7 g/day for those ≥65 years and 21.6 g/day for
285
those <65 years) or to switch to placebo (21.2 g/day for both patients ≥65 and <65
286
years). During Part B, the mean daily dose in the patiromer group was 19.9 g/day in
287
patients ≥65 years and 22.7 g/day in patients <65 years. During Part B, dose titrations
288
were permitted only in the patiromer group (and during the first 4 weeks when the
289
primary efficacy endpoint was under evaluation, only if serum potassium was <3.8
290
mEq/L or >5.5 mEq/L). Over the entire phase, patiromer dose increases were reported
291
in 3 (10%) patients ≥65 years and in 5 (19.2%) patients <65 years.
292 293
Safety
294
During Part A and its safety follow-up period, 47% of the patients ≥65 years and 46% of
295
those <65 years reported ≥1 adverse event (Table 2). A total of 10 (7.6%) patients ≥65
296
years and 5 (4.5%) patients <65 years reported an adverse event that led to study
297
discontinuation during the initial treatment phase. Two (1.5%) patients ≥65 years and 1
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298
(0.9%) patient <65 years reported a total of 6 non-fatal serious adverse events ; none of
299
these were considered by the investigator as related to patiromer.
300
The proportions of patients who reported at least 1 adverse event during Part B
301
and its safety follow-up period were generally similar in patients on patiromer vs placebo
302
(Table 3). Two (6.9%) patients ≥65 years who were on patiromer reported constipation;
303
in both, the adverse event was related to patiromer but was not severe or serious. Two
304
(3.3%) patients ≥65 years (1 patiromer, 1 placebo) and none <65 years reported an
305
adverse event that led to study discontinuation during the withdrawal phase. One
306
patient ≥65 years who was on placebo during Part B reported an serious adverse event
307
(mesenteric vessel thrombosis) that led to death; the serious adverse event was
308
reported 36 days after the last dose of patiromer in Part A and was considered by the
309
investigator as not related to patiromer and by the Safety Review Board as not related
310
to hypokalemia or hyperkalemia.
311
Mean serum Mg2+ remained within the normal range during the study. Predefined
312
measures of serum Mg2+ <1.4 mg/dL and serum K+ <3.5 mEq/L (Part A) and <3.8
313
mEq/L (Part B) were infrequent (Tables 2 and 3). In the 8 patients with serum Mg2+
314
<1.4 mg/dL during patiromer treatment, Mg2+ levels increased during follow-up after
315
patiromer was discontinued, regardless of age group. Hypomagnesemia was reported
316
as an adverse event in Part A for 8 patients (5 patients ≥65 years of age and 3 patients
317
<65 year of age; Table 2); and blood Mg2+ decreased was reported as an adverse event
318
in 1 patient <65 years of age. Of note, only 2 (both ≥65 years) of the 9 patients with
319
these adverse events had prespecified serum Mg2+ <1.4 mg/dL (1.3 mg/dL in both
320
patients at or after the adverse events were recorded). All 9 patients received Mg2+
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321
supplementation and none were discontinued from Part A due to adverse events. In
322
Part B, as shown in Table 3, no patients had serum Mg2+ <1.4 mg/dL.
323
Hypomagnesemia was reported as an adverse event in 3 patients (serum Mg2+, 1.7–1.8
324
mg/dL at the time of the event; 2 patients were ≥65 years [1 on patiromer, 1 on placebo]
325
and 1 patient was <65 years and on placebo); and a decrease in blood Mg2+ was
326
reported in 1 patient ≥65 years receiving placebo (serum Mg2+, 1.7 mg/dL at the time of
327
the event). Three of these 4 patients received Mg2+ supplementation and none were
328
discontinued from Part B due to adverse events. No patient had both hypokalemia and
329
hypomagnesemia at any time during the study.
330 331
DISCUSSION
332
This prespecified subgroup analysis of patients aged ≥65 years from the OPAL-HK
333
study shows that patiromer is effective in managing hyperkalemia in patients with
334
chronic kidney disease on RAASi, regardless of age. The effect on lowering serum K+
335
during the initial treatment phase was similar in patients ≥65 years and <65 years, and
336
>96% of all patients achieved normokalemia (serum K+ 3.5–<5.1 mEq/L) at some point
337
during the phase. The magnitude of serum K+ decrease in response to patiromer in
338
patients ≥75 years appears to be consistent with the current findings.38 Of note, more
339
than 50% of patients in each age subgroup were on loop or thiazide diuretics at
340
baseline; however, a previously published analysis of OPAL-HK data showed similar
341
magnitude and time course of reductions in serum K+ in patients on and not on
342
diuretics.45
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343
Patients aged ≥65 years are more likely to have multiple risk factors for
344
hyperkalemia as a result of age-related comorbidities—such as chronic kidney disease,
345
diabetes, and heart failure—and the use of guideline-recommended RAASi therapy for
346
these conditions.2,3,22,23 Patients in both groups were at similar risk for persistent
347
hyperkalemia as they had similarly low eGFRs, similar proportions of patients in both
348
groups had type 2 diabetes, and all were on RAASi at baseline. The study population
349
represents a real-world population at risk for hyperkalemia who can benefit from RAASi
350
therapy.
351
Our result that the median serum K+ increased in patients—both ≥65 and <65
352
years—who switched to placebo, but not in those who continued patiromer, during the
353
randomized withdrawal phase demonstrates that daily patiromer is needed to maintain
354
normokalemia. Consistent with this, fewer recurrent hyperkalemia events occurred in
355
patients in both age groups who continued patiromer compared with those who
356
switched to placebo. The rate of recurrent hyperkalemia was lower in older vs. younger
357
patients when defined as serum K+ ≥5.1 mEq/L; however, given that there was no
358
difference between age groups in the rate of recurrent hyperkalemia based on serum K+
359
≥5.5 mEq/L, this difference is likely not clinically relevant. As a result of the reduced rate
360
of recurrent hyperkalemia, more patients who continued patiromer in both age groups
361
were able to maintain their RAASi therapy. These exploratory data suggest that
362
patiromer may enable patients with chronic kidney disease, including older patients, to
363
maintain their guideline-recommended RAASi therapy. In the current analysis, more
364
than 50% of patients ≥65 years had heart failure; in a previous report, heart failure
365
patients treated with patiromer in OPAL-HK showed decreases in serum K+ similar to
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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366
those seen in the current analysis, with similar proportions of patients achieving
367
normokalemia and remaining on RAASi at study end.42 Hyperkalemia also likely
368
contributes to the cost of managing patients with chronic kidney disease and/or heart
369
failure, both directly (more hospital visits and longer inpatient stays) and indirectly
370
(RAASi discontinuation or dose reduction).25,26,46 The ability of patiromer to lower serum
371
K+ and to prevent recurrent hyperkalemia may also provide economic value.
372
Patiromer was well tolerated in patients regardless of age. During the initial
373
treatment phase, mild-to-moderate gastrointestinal events (eg, constipation, diarrhea,
374
nausea) were the most frequently reported class of adverse events in both subgroups,
375
while the specific events of constipation and diarrhea occurred more frequently in
376
patients ≥65 years. All other adverse events and events leading to study drug
377
discontinuation occurred at similarly low rates in both groups. As described previously,
378
few serious adverse events occurred during the study; none were related to patiromer.43
379
The mean serum Mg2+ levels remained relatively unaltered in patients ≥65 years and
380
<65 years throughout both phases of study and occurrences of serum Mg2+ <1.4 were
381
infrequent and in all cases serum Mg2+ increased during follow-up after patiromer was
382
discontinued. While adverse events of hypomagnesemia or blood Mg2+ decreased
383
occurred in 5 patients ≥65 years and 4 patients <65 years in Part A, only 2 of these
384
patients had serum Mg2+ <1.4 mg/dL at any time during the study. Patients who are at
385
an increased risk for hypomagnesemia (eg, those with diabetes and those treated with
386
loop diuretics or proton pump inhibitors) may warrant closer attention during patiromer
387
treatment. The prescribing information for patiromer recommends that magnesium
388
supplementation be considered for patients who develop low serum Mg2+ levels during
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
17 Page 17 of 39
389
treatment.40 Serum K+ levels <3.8 mEq/L (predefined as hypokalemia in Part A)
390
occurred at low frequency 4% and 2% in patients ≥65 years and <65 years,
391
respectively, and was reversible by patiromer dose adjustment.
392
Finally, as noted previously, patiromer uses calcium as the counter-exchange
393
ion, with approximately 1.6 g of calcium per 8.4 g of patiromer.47 As reported by
394
Bushinsky and colleagues, at the maximal recommended daily dose (25.2 g/day),
395
patiromer administration in healthy adults increased urine calcium by 73 mg/day,
396
suggesting that only a small fraction of the calcium released from patiromer is available
397
for absorption. At the same time, urine phosphate decreased by 64 mg/day, suggesting
398
that some of the released calcium may bind phosphate, which is then excreted in the
399
stool as relatively insoluble salts.48 Nonetheless, clinicians will need to weigh the risk of
400
a potential small increase in calcium absorption compared with the risk of hyperkalemia
401
in patients with chronic kidney disease.
402
Limitations of OPAL-HK have been described previously.43 Briefly, this was a
403
short-term and single-blind study, and the number of patients in the two age groups that
404
received patiromer or placebo during the randomized withdrawal phase was relatively
405
small. However, similar reductions in serum K+ in patients ≥65 years (n=182) and in
406
those <65 years (n=122) were observed in a larger, phase 2 trial of patiromer (personal
407
communication, M. Weir).
408 409
CONCLUSIONS
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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410
Treatment with patiromer significantly reduced serum K+ and maintained normokalemia
411
in hyperkalemic patients aged ≥65 years with chronic kidney disease who were on
412
RAASi. As a consequence, significantly more patiromer-treated patients were able to
413
continue guideline-recommended RAASi therapy. Patiromer was well tolerated in
414
patients aged ≥65 years with low rates of discontinuations.
415
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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416
ACKNOWLEDGMENTS
417
This study was funded by Relypsa, Inc. Editorial assistance was provided by Narender
418
Dhingra, MBBS, PhD; and was funded by Relypsa, Inc.
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Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
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419
References (48 of 40 allowed)
420
1.
worldwide. MMWR Morb Mortal Wkly Rep. 2003;52:101-104,106.
421 422
Centers for Disease Control and Prevention. Trends in aging--United States and
2.
Stevens LA, Viswanathan G, Weiner DE. Chronic kidney disease and end-stage
423
renal disease in the elderly population: current prevalence, future projections,
424
and clinical significance. Adv Chronic Kidney Dis. 2010;17:293-301.
425
3.
failure in elderly persons, 1994-2003. Arch Intern Med. 2008;168:418-424.
426 427
4.
5.
6.
Kemper P, Komisar HL, Alecxih L. Long-term care over an uncertain future: what can current retirees expect? Inquiry. 2005;42:335-350.
432 433
Knickman JR, Snell EK. The 2030 problem: caring for aging baby boomers. Health Serv Res. 2002;37:849-884.
430 431
Tobias DE, Sey M. General and psychotherapeutic medication use in 328 nursing facilities: A year 2000 national survey. Consult Pharm. 2001;16:54-64.
428 429
Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart
7.
Hines AL, Barrett ML, Jiang HJ, et al. Conditions with the largest number of adult
434
hospital readmissions by payer, 2011: Statistical brief #172. Healthcare Cost and
435
Utilization Project (HCUP) Statistical Briefs. Rockville (MD). 2006.
436
8.
failure in elderly persons, 2001-2005. Arch Intern Med. 2008;168:2481-2488.
437 438
Curtis LH, Greiner MA, Hammill BG, et al. Early and long-term outcomes of heart
9.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
439
angiotensin-receptor antagonist irbesartan in patients with nephropathy due to
440
type 2 diabetes. N Engl J Med. 2001;345:851-860.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
21 Page 21 of 39
441
10.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and
442
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N
443
Engl J Med. 2001;345:861-869.
444
11.
Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors
445
and progression of nondiabetic renal disease. A meta-analysis of patient-level
446
data. Ann Intern Med. 2001;135:73-87.
447
12.
Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal
448
outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA.
449
2001;285:2719-2728.
450
13.
Effects of enalapril on mortality in severe congestive heart failure. Results of the
451
Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The
452
CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435.
453
14.
Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on survival in patients with
454
reduced left ventricular ejection fractions and congestive heart failure. The
455
SOLVD Investigators. N Engl J Med. 1991;325:293-302.
456
15.
Yusuf S, Pitt B, Davis CE, et al. Effect of enalapril on mortality and the
457
development of heart failure in asymptomatic patients with reduced left
458
ventricular ejection fractions. The SOLVD Investigators. N Engl J Med.
459
1992;327:685-691.
460
16.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting
461
enzyme inhibitors on mortality and morbidity in patients with heart failure.
462
Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450-1456.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
22 Page 22 of 39
463
17.
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality
464
and morbidity in patients with chronic heart failure: the CHARM-Overall
465
programme. Lancet. 2003;362:759-766.
466
18.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity
467
and mortality in patients with severe heart failure. Randomized Aldactone
468
Evaluation Study Investigators. N Engl J Med. 1999;341:709-717.
469
19.
National Kidney Foundation K/DOQI clinical practice guidelines for chronic
470
kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.
471
2002;39:S1-S266.
472
20.
Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO
473
clinical practice guideline for the evaluation and management of CKD. Am J
474
Kidney Dis. 2014;63:713-735.
475
21.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the
476
management of heart failure: executive summary: a report of the American
477
College of Cardiology Foundation/American Heart Association Task Force on
478
practice guidelines. Circulation. 2013;128:1810-1852.
479
22.
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update
480
on New Pharmacological Therapy for Heart Failure: An Update of the 2013
481
ACCF/AHA Guideline for the Management of Heart Failure: A Report of the
482
American College of Cardiology/American Heart Association Task Force on
483
Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll
484
Cardiol. 2016;68:1476-1488.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
23 Page 23 of 39
485
23.
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis
486
and treatment of acute and chronic heart failure: The task force for the diagnosis
487
and treatment of acute and chronic heart failure of the European Society of
488
Cardiology (ESC). Developed with the special contribution of the Heart Failure
489
Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.
490
24.
Diabetes Care. 2017;40:S88-S98.
491 492
American Diabetes Association. 10. Microvascular complications and foot care.
25.
Epstein M, Alvarez PJ, Reaven NL, et al. Evaluation of clinical outcomes and
493
costs based on prescribed dose level of renin-angiotensin-aldosterone system
494
inhibitors. Am J Manag Care 2016;22 (Suppl 11):S313-S326.
495
26.
Ouwerkerk W, Voors AA, Anaker SD, et al. Determinantsand clincical outcome of
496
uptitration of ACE-inhibitors and beta-blockers in patiients with heart failure: a
497
prospective European study. Eur Heart J 2017;
498
http://dx.doi.org/10.1093/eurheartj/ehx026 [Epub ahead of print].
499
27.
angiotensin-aldosterone system. N Engl J Med. 2004;351:585-592.
500 501
28.
29.
Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol. 2010;5:531-548.
504 505
Perazella MA, Mahnensmith RL. Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med. 1997;12:646-656.
502 503
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-
30.
Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-
506
converting enzyme inhibitors. How much should we worry? Arch Intern Med.
507
1998;158:26-32.
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
24 Page 24 of 39
508
31.
significance in chronic kidney disease. Arch Intern Med. 2009;169:1156-1162.
509 510
Einhorn LM, Zhan M, Hsu V, et al. THe frequency of hyperkalemia and its
32.
Berkova M, Berka Z, Topinkova E. Arrhythmias and ECG changes in life
511
threatening hyperkalemia in older patients treated by potassium sparing drugs.
512
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014;158:84-91.
513
33.
Genovesi S, Valsecchi MG, Rossi E, et al. Sudden death and associated factors
514
in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant.
515
2009;24:2529-2536.
516
34.
Miao Y, Dobre D, Heerspink HJ, et al. Increased serum potassium affects renal
517
outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the
518
Angiotensin II Antagonist Losartan (RENAAL) trial. Diabetologia. 2011;54:44-50.
519
35.
Epstein M, Pitt B. Recent advances in pharmacological treatments of
520
hyperkalemia: focus on patiromer. Expert Opin Pharmacother. 2016;17:1435-
521
1448.
522
36.
Epstein M, Reaven NL, Funk SE, et al. Evaluation of the treatment gap between
523
clinical guidelines and the utilization of renin-angiotensin-aldosterone system
524
inhibitors. Am J Manag Care. 2015;21:S212-S220.
525
37.
current data and opportunities for the future. Hypertension. 2015;66:731-738.
526 527
38.
530
Kumar R, Kanev L, Woods SD, et al. Managing hyperkalemia in high-risk patients in long-term care. Am J Manag Care Supplement. 2017;23:S27-S36.
528 529
Pitt B, Bakris GL. New potassium binders for the treatment of hyperkalemia:
39.
Li L, Harrison SD, Cope MJ, et al. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross-linked polymer that lowers serum potassium
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
25 Page 25 of 39
531
concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther.
532
2016;21:456-465.
533
40.
Veltassa (patiromer) for oral suspension [package insert]: Relypsa, Inc.; 2016.
534
41.
European Medicines Agency. Veltassa.
535
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicine
536
s/004180/human_med_002141.jsp&mid=WC0b01ac058001d124. Accessed
537
August 15, 2017.
538
42.
Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum
539
potassium and preventing recurrent hyperkalaemia in patients with heart failure
540
and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail. 2015;17:1057-
541
1065.
542
43.
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney
543
disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med.
544
2015;372:211-221.
545
44.
Bakris GL, Pitt B, Weir MR, et al. Effect of patiromer on serum potassium level in
546
patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN
547
randomized clinical trial. JAMA. 2015;314:151-161.
548
45.
Weir MR, Mayo MR, Garza D, et al. Effectiveness of patiromer in the treatment of
549
hyperkalemia in chronic kidney disease patients with hypertension on diuretics. J
550
Hypertens. 2017;35(suppl 1):S57-S63.
551 552
46.
Polson M, Evangelatos T, Lord T, et al. Clinical and economic impact of hyperkalemia in patients with chronic kidney disease and heart failure (abstract).
+
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
26 Page 26 of 39
553
Academy of Managed Care Pharmacy Nexus. Vol 22. National Harbor, Maryland:
554
J Manag Care Spec Pharm; 2016:S43.
555
47.
2016;4:237.
556 557 558
Bakris G, Weir M, Epstein M. Letter to the Editor. J Cardiovasc Dis Diagn.
48.
Bushinsky DA, Spiegel DM, Gross C, et al. Effect of patiromer on urinary ion excretion in healthy adults. Clin J Am Soc Nephrol. 2016;11:1769-1776.
559 560 561 562
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Figures
564 565
Figure 1 Effect of patiromer on serum K+ in patients aged ≥65 and <65 years during the
566
initial treatment phase (Part A). Estimates of mean (SE) serum K+ by visit
567
were based on models that included presence or absence of heart failure and
568
presence or absence of type 2 diabetes. The post-baseline models also
569
included the baseline serum K+ value. Baseline and day 3 means were
570
estimated using ANOVA models; estimates at weeks 1–4 were based on
571
mixed models with repeated measures. ANOVA, analysis of variance; K +,
572
potassium; SE, standard error.
573
[Please print the Figure in color at either 1.5- or double-column width]
574 575
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576 577
Figure 2 Proportion of patients with recurrent hyperkalemia (panel A, ≥5.5 mEq/L; panel
578
B ≥5.1 mEq/L) at any time through 8 weeks of the randomized withdrawal
579
phase (Part B). HK, hyperkalemia; K+, potassium.
580
[Please print the Figure in color at single-column width]
581 582
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583 584
Figure 3 Proportion of patients who required management of recurrent hyperkalemia
585
and who remained on RAASi at the end of the randomized withdrawal phase
586
(Part B). *The protocol required different interventions for the management of
587
recurrent hyperkalemia (ie, RAASi dose reduction or discontinuation in the
588
placebo group and patiromer dose increase or RAASi discontinuation in the
589
patiromer group). †Could be at the final visit (week 8), or earlier if the patient
590
discontinued. HK, hyperkalemia; K+, potassium; RAASi, renin-angiotensin-
591
aldosterone-system inhibitors.
592
[Please print the Figure in color at single-column width]
593
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594 595
Figure 4 Time to RAASi discontinuation during the randomized withdrawal phase (Part
596
B). Circles indicate censored observations. RAASi, renin-angiotensin-
597
aldosterone-system inhibitors.
598
[Please print the Figure in color at either 1.5- or double-column width]
599 600
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601 602
Table 1 Baseline Demographic and Clinical Characteristics at Baseline in the Initial Treatment Phase (Part A) by Age Group Parameter
603 604 605 606 607 608 609 610 611
≥65 years (n = 131) 76 (58.0) 71.7 (4.4)
<65 years (n = 112) 64 (57.1) 55.5 (8.6)
Male, n (%) Age (years), mean (SD) <65 years 65-69 years 70-74 years ≥75 years White, n (%) Chronic kidney disease stage (eGFR in mL/min/1.73 m2), n (%)* Stage 2† (60–<90) Stage 3A (45–<60) Stage 3B (30–<45) Stage 4/5 (<30) Type 2 diabetes mellitus, n (%) Heart failure, n (%) Time since diagnosis (years), mean (SD) Myocardial infarction, n (%) Hypertension, n (%) eGFR (mL/min/1.73 m2), mean (SD)
12 (9.2) 32 (24.4) 31 (23.7) 56 (42.7)
10 (8.9) 17 (15.2) 32 (28.6) 53 (47.3)
78 (59.5) 68 (51.9) 4.0 (5.0) 34 (26.0) 127 (96.9) 36.8 (16.1)‡
61 (54.5) 34 (30.4) 2.7 (3.2) 26 (23.2) 109 (97.3) 33.9 (16.3)‡
Serum blood urea nitrogen (mg/dL), mean (SD) Serum creatinine (mg/dL), mean (SD) Serum K+ (mEq/L), mean (SD)§ n
37.0 (17.0) 1.92 (0.8)¶ 5.59 (0.54) 130
41.8 (19.1) 2.34 (1.2)¶ 5.56 (0.49) 108
129 (98.5)
46.1% 18.5% 18.5% 16.8%
110 (98.2)
*Classification of chronic kidney disease stage at baseline was determined by central laboratory eGFR values. None of the patients had stage 1 chronic kidney disease. † Approximately 9% of patients in each subgroup who met the entry criteria based on their local laboratory eGFR values were reclassified on the basis of their central eGFR values as having stage 2 chronic kidney disease at baseline. ‡P = NS and ¶P <0.01 for difference between age groups (one-way ANOVA). §By central laboratory measurements. ANOVA, analysis of variance; eGFR, estimated glomerular filtration rate; K+, potassium; SD, standard deviation.
612
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613 614
Table 2 Adverse Events During Initial Treatment Phase (Part A) and Its Safety Followup by Age Group ≥65 years (n = 131) 62 (47.3)
<65 years (n = 112) 52 (46.4)
19 (14.5) 7 (5.3) 5 (3.8) 5 (3.8) 4 (3.1) 2 (1.5) 4 (3.1) 2 (1.5) 0 (0)
7 (6.3) 1 (0.9) 3 (2.7) 3 (2.7) 3 (2.7) 5 (4.5) 2 (1.8) 4 (3.6) 4 (3.6)
36 (27.5) 17 (13) 6 (4.6) 5 (3.8)
17 (15.2) 7 (6.3) 1 (0.9) 2 (1.8)
1 (0.8) 2 (1.5)
0 (0) 1 (0.9)
5 (4.0)
2 (1.8)
<1.4 mg/dL
5 (4.0)
3 (2.7)
<1.2 mg/dL
0
0
Adverse Event, n (%)* At least 1 adverse event Most common adverse events† Constipation Diarrhea Hypomagnesemia Nausea Anemia Worsening of chronic kidney disease Hyperkalemia Left ventricular hypertrophy Reduced GFR Most common patiromer-related adverse events† Any patiromer-related adverse event Constipation Diarrhea Hypomagnesemia Other adverse events of interest Edema (peripheral) At least 1 serious adverse event Prespecified electrolytes of interest‡ Serum K+ <3.5 mEq/L Serum Mg2+
615 616 617 618 619
*Based on Safety Population. †Occurring in >3% of patients in either subgroup; presented by descending number of patients for both subgroups combined. ‡Available for 126 patients ≥65 years and 111 patients <65 years. GFR, glomerular filtration rate; K+, potassium; Mg2+, magnesium.
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620 621 622
Table 3 Adverse Events During Withdrawal Phase (Part B) and Its Safety Follow-up by Age Group <65 years
≥65 years Patiromer (n = 29)
Placebo (n = 31)
Patiromer (n = 26)
Placebo (n = 21)
15 (51.7)
17 (54.8)
11 (42.3)
9 (42.9)
Constipation
2 (6.9)
0
0
0
Nausea
2 (6.9)
0
0
0
Headache
1 (3.4)
2 (6.5)
1 (3.8)
2 (9.5)
Influenza
1 (3.4)
1 (3.2)
0
2 (9.5)
Hyperkalemia
0
2 (6.5)
1 (3.8)
0
Hepatic enzyme increased
0
2 (6.5)
1 (3.8)
0
Hypertension
0
0
0
3 (14.3)
4 (13.8)
2 (6.5)
0
0
2 (6.9)
0
0
0
0 0
0 1 (3.2)
0 0
0 0
2 (6.9)
1 (3.2)
1 (3.9)
0
0 0
0 0
0 0
0 0
Adverse Event, n (%)* At least 1 adverse event Most common adverse events†
Most common patiromer-related adverse events Any patiromer-related adverse event Constipation Adverse events of interest Edema (peripheral) At least 1 serious adverse event Prespecified electrolytes of interest Serum K+ <3.8 mEq/L‡ Serum Mg2+ <1.4 mg/dL <1.2 mg/dL 623 624 625 626 627 628
†
*Based on Safety Population. †Occurring in ≥2 patients in any subgroup; presented in descending order of incidence in patients ≥65 on patiromer. ‡During the withdrawal phase and its follow-up period, hypokalemia was predefined as serum K + <3.8 mEq/L, the protocol-specified criterion for study withdrawal. K+, potassium; Mg2+, magnesium.
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629
Supplementary Appendix
630
This appendix has been provided by the authors to give readers additional information
631
about their work.
632
Supplement to: Weir MR, Bushinsky DA, Benton WW, et al. Effect of Patiromer on
633
Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients on Renin-
634
Angiotensin-Aldosterone-System Inhibitors
635 636 637 638
Table of Contents Supplementary Figure 1 Change in serum K+ from baseline to week 4 of the randomized withdrawal phase (Part B) by age group. ................................................... 36
639 640 641
Supplementary Figure 2 Kaplan-Meier estimates of the time to time to first serum potassium level ≥5.5 mEq/L (Panels A and B) and ≥5.1 mEq/L (Panels C and D) by age subgroup. ...................................................................................................................... 37
642 643
Supplementary Table 1 Concomitant Medications at Baseline in the Initial Treatment Phase (Part A) by Age Group........................................................................................ 38
644
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645
Supplementary Figure 1 Change in serum K+ from baseline to week 4 of the
646
randomized withdrawal phase (Part B) by age group.
647
*For comparison between treatment groups in mean rank change. K+, potassium.
648 649
36 Page 36 of 39
650 651
Supplementary Figure 2 Time to first serum potassium level ≥5.5 mEq/L (Panels A and B) and ≥5.1 mEq/L (Panels C and D) by age subgroup.
652
653
654 655
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656
657 658
Supplementary Table 1 Concomitant Medications at Baseline in the Initial Treatment Phase (Part A) by Age Group. ≥65 years <65 years Moderate/ Moderate/ Concomitant Total Mild HK Severe Mild HK Severe Total Medication (n = (n = 53) HK (n = 39) HK (n = 112) 131) (n = 78) (n = 73) Number of 6.8 medications, mean 6.6 (2.9) 6.7 (2.9) 6.1 (3.5) 5.6 (2.9) 5.8 (3.1) (2.9) (SD) 53 131 (100) (100) RAASi medication, n 39 (100) 38 90 (%) 30 112 (71.7) 78 (100) (68.7) 73 (100) ACE inhibitor (76.9) (100) 19 52 (66.7) 48 50 (68.5) ARB 14 80 (71.4) (35.8) 29 (37.2) (36.6) 30 (41.1) Aldosterone (35.9) 44 (39.3) 10 7 (9.0) 17 4 (5.5) antagonist 1 (2.6) 5 (4.5) (18.9) 0 (13.0) 1 (1.4) Renin inhibitor 0 1 (0.9) 1 (1.9) 10 (12.8) 1 (0.8) 12 (16.4) * Dual RAASi 6 (15.4) 18 (16.1) 13 37 (47.4) 23 27 (37.0) On maximal RAASi 15 42 (37.5) (24.5) (17.6) † dose (38.5) 27 64 (50.9) (48.9) Non-RAASi, nondiuretic antihypertensives, n (%) Beta blocker Calcium channel blocker Alpha blocker
40 (75.5) 30 (56.6) 18 (34.0) 8 (15.1)
Non-RAASi diuretics, n (%) Thiazide or thiazidelike Loop Insulin, n (%) Long-acting Intermediate-acting Short-acting Combination +
28 (52.8) 12 (22.6) 18 (34.0) 12 (22.6) 4 (7.5) 2 (3.8) 6 (11.3)
67 (85.9) 45 (57.7) 43 (55.1) 8 (10.3)
41 (52.6) 21 (26.9) 26 (33.3) 11 (14.1) 6 (7.7) 2 (2.6) 3 (3.8) 3 (3.8)
107 (81.7) 75 (57.3) 61 (46.6) 16 (12.2) 69 (52.7) 33 (25.2) 44 (33.6) 23 (17.6) 10 (7.6) 4 (3.1) 9 (6.9)
23 (59.0) 16 (41.0) 19 (48.7) 2 (5.1) 22 (56.4) 13 (33.3) 11 (28.2) 8 (20.5) 4 (10.3) 1 (2.6) 6 (15.4) 0 (0)
Patiromer Lowers Serum K in Older Chronic Kidney Disease Patients
56 (76.7) 37 (50.7) 32 (43.8) 4 (5.5)
79 (70.5) 53 (47.3) 51 (45.5) 6 (5.4)
41 (56.2) 24 (32.9) 22 (30.1)
63 (56.3) 37 (33.0) 33 (29.5)
24 (32.9) 8 (11.0) 8 (11.0) 20 (27.4) 2 (2.7)
32 (28.6) 12 (10.7) 9 (8.0) 26 (23.2) 2 (1.8) 38 Page 38 of 39
Non-insulin antidiabetic, n (%) Biguanides Sulfonylureas Others Magnesium supplementation, n (%) Warfarin, n (%)
4 (7.5)
7 (5.3)
23 (43.4) 10 (18.9) 15 (28.3) 3 (5.7)
33 (42.3) 14 (17.9) 25 (32.1) 3 (3.8)
56 (42.7) 24 (18.3) 40 (30.5) 6 (4.6)
11 (28.2) 4 (10.3) 7 (17.9) 3 (7.7)
19 (26.0) 6 (8.2) 17 (23.3) 0
30 (26.8) 10 (8.9) 24 (21.4) 3 (2.7)
5 (9.4)
8 (10.3)
13 (9.9)
3 (7.7)
8 (11.0)
11 (9.8)
5 (9.4)
8 (10.3)
13 (9.9)
3 (7.7)
0
3 (2.7)
659 660
*Any combination of two or more of the following: ACE inhibitor, ARB, aldosterone
661
antagonist, and renin inhibitor. †As assessed by the investigator in accordance with
662
local standards of care. ACE, angiotensin-converting enzyme; ARB, angiotensin II
663
receptor blocker; HK, hyperkalemia; RAASi, renin-angiotensin-aldosterone system
664
inhibitors; SD, standard deviation.
665
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