Long-term Patiromer Use and Outcomes Among US Veterans With Hyperkalemia and CKD: A Propensity-Matched Cohort Study.

Rationale & Objective: Patiromer is a potassium binder approved for the long-term management of hyperkalemia. Although patiromer use among patients with advanced chronic kidney disease (CKD) has been shown to reduce the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, it remains unclear whether patiromer can improve clinical outcomes. The aim of this study was to examine the association of long-term patiromer use with clinical outcomes among hyperkalemic patients with CKD. Study Design: This was a longitudinal observational study. Setting & Participants: We evaluated a national cohort of 854,217 US Veterans who had at least 1 serum potassium measurement of ≥5.1 mEq/L and were treated at US Department of Veterans Affairs health care facilities between January 2016 and September 2019. Exposure: The exposure was long-term patiromer use. Outcomes: The outcomes were as follows: (1) composite endpoint of kidney failure with replacement therapy (KFRT) or all-cause death and (2) all-cause death including the post-KFRT period. Analytical Approach: Cox proportional Fine-Gray subdistribution hazard models were used in a propensity-matched cohort. Results: Among 2,004 patients who ever used patiromer during the study period (0.2% of the cohort), 666 met the criteria for long-term patiromer use. We matched 308 long-term patiromer users to 308 nonusers based on propensity scores. The median estimated glomerular filtration rate was 23.5 mL/min/1.73m2, and the median potassium level was 5.2 mEq/L. Approximately 45% were on renin-angiotensin system inhibitor(s) at baseline. During follow-up, 93 patients developed KFRT, and 134 patients died. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome (HR, 0.74; 95% CI, 0.53-1.01; P = 0.06) and a 41% lower risk of all-cause mortality (HR, 0.59; 95% CI, 0.41-0.84; P = 0.003). Limitations: The study cohort included mostly male veterans with relatively short follow-up periods. Conclusions: Long-term patiromer use was associated with a lower risk of all-cause mortality among patients with CKD and hyperkalemia. Long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD. Plain-Language Summary: Hyperkalemia is a common complication of chronic kidney disease (CKD) and can result in the discontinuation of renin-angiotensin-aldosterone system inhibition therapy, a cornerstone of CKD management. Patiromer is a new potassium binder approved for the long-term management of hyperkalemia, but it remains unclear whether patiromer can improve clinical outcomes. We examined a cohort of US Veterans with hyperkalemia between January 2016 and September 2019 and found that patiromer use was uncommon for treating hyperkalemia during this study period. We then matched 308 long-term patiromer users and 308 nonusers based on propensity scores. Long-term patiromer users, when compared to nonusers, experienced a 26% lower risk of the composite outcome and a 41% lower risk of all-cause mortality. These findings indicate that long-term potassium binder use for hyperkalemia may improve clinical outcomes in CKD.

Impact of initiating oral anticancer agents for leukemia on adherence to medications for multiple chronic conditions.

INTRODUCTION: Increased use of oral anticancer agents (OAAs) has empowered adults with chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML) to manage their therapy, but this shift may complicate medication use, particularly among adults with multiple chronic conditions (MCC). METHODS: This retrospective cohort study used 2013-2018 commercial and Medicare claims data to assess medication use in adults with CML or CLL. To be included, patients must have been at least 18 years old, diagnosed with and had 2+ claims for an OAA indicated for either CML or CLL, continuously enrolled 12 months before and after OAA initiation, and treated for (2+ fills) at least two select chronic conditions. Proportion of days covered (PDC) determined medication adherence and was compared for 12 months before and after OAA initiation by Wilcoxon signed-rank tests, McNemar's tests, and difference-in-differences models. RESULTS: Among CLL patients, mean OAA adherence in the first year of therapy was 79.8% (SD: 21.1) and 74.7% (SD: 24.9) for commercial and Medicare patients, respectively; mean adherence for CML patients was 84.5% (SD: 15.8) and 80.1% (SD: 20.1) for commercial and Medicare patients, respectively. Adherence and the proportion adherent (PDC ≥ 80%) to comorbid therapies was generally unchanged following OAA initiation. Consistently unremarkable changes in MCC adherence were observed in 12-month difference-in-differences models, but significant decline was observed in MCC adherence after 6 months of OAA use. CONCLUSIONS: OAA initiation among adults with CML or CLL was not associated with significant, initial changes to adherence to medications for chronic diseases.

Medication Adherence Among Adults With Comorbid Chronic Conditions Initiating Oral Anticancer Agent Therapy for Multiple Myeloma.

PURPOSE: Increased use of oral anticancer agents (OAAs) has empowered adults with multiple myeloma (MM) to manage their oncolytic therapy, but such a shift may result in issues with medication use, particularly among patients being concurrently treated for pre-existing, multiple chronic conditions. METHODS: This retrospective cohort study used 2013-2018 commercial and Medicare claims data to assess medication use in adults with MM. To be included, adults (18 years and older) must have been diagnosed with and had 2+ claims for an OAA, had continuous enrollment for 12 months before and after OAA initiation, and have been previously diagnosed with and had prescription fills for 2+ select chronic conditions. The proportion of days covered metric assessed medication adherence and was compared for 12 months before and after the OAA initiation by Wilcoxon signed-rank tests, McNemar's tests, and difference-in-differences models. RESULTS: The mean OAA adherence in the first year of therapy was 58.3% (standard deviation: 24.5) and 65.1% (standard deviation: 27.01) for commercial and Medicare patients, respectively. Adherence and the proportion adherent (proportion of days covered ≥ 80%) to comorbid therapies generally declined in the first year after OAA initiation. Changes in medication use were particularly noticeable among those on antihypertensive therapy: adjusted analyses uncovered a 2.5% (Medicare) and 5.2% (commercial) difference in adherence to these medications between those initially adherent and nonadherent to OAA therapy (both P < .05). CONCLUSION: Initiating OAA therapy in adults with MM may complicate an already complex treatment regimen, resulting in poor overall medication adherence in patients with multiple comorbid conditions.

Predialysis Potassium Variability and Postdialysis Mortality in Patients With Advanced CKD.

INTRODUCTION: Patients with advanced non-dialysis-dependent chronic kidney disease (NDD-CKD) are prone to potassium (K) imbalances due to reduced kidney function. Both hypo- and hyperkalemia are associated with increased mortality; however, it is unclear if K variability before dialysis initiation is associated with outcomes after dialysis initiation. METHODS: We identified 34,167 US veterans with advanced NDD-CKD transitioning to dialysis between October 1, 2007, through March 31, 2015, who had at least 1 K measurement each year over a 3-year period before transition (3-year prelude). For each patient, a linear mixed-effects model was used to regress K over time (in years) over the 3-year prelude to derive K variability (square root of the average squared distance between the observed and estimated K). The main outcomes of interest were 6-month all-cause and cardiovascular mortality after dialysis initiation. Multivariable Cox and Fine-Gray competing risk regression adjusted for 3-year prelude K intercept, K slope (per year), demographics, smoking status, comorbidities, length of hospitalizations, body mass index, vascular access type, medications, average estimated glomerular filtration rate, and number of K measurements over the 3-year prelude were used to assess the association of K variability (expressed as quartiles) with all-cause and cardiovascular mortality, respectively. RESULTS: Higher prelude K variability was associated with higher multivariable-adjusted risk of all-cause mortality but not cardiovascular mortality (adjusted hazard/subhazard ratios [95% confidence interval] for highest quartile [vs. lowest] of K variability, 1.14 [1.03-1.25] and 0.99 [0.85-1.16] for all-cause and cardiovascular mortality, respectively). CONCLUSION: Higher K variability is associated with higher all-cause mortality after dialysis initiation.

Association between Nrf2 and CDKN2A expression in patients with end-stage renal disease: a pilot study.

Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A (CDKN2A, or p16INK4a, a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with CDKN2A expression, using Spearman's rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and CDKN2A expression (rho=-0.51, P=0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, P=0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with CDKN2A expression (ß coefficient=-1.51, P=0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.

Medication Adherence, Health Care Utilization, and Costs Among Patients Initiating Oral Oncolytics for Multiple Myeloma or Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

BACKGROUND: Oral oncolytic therapies have improved survival in hematologic cancers, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and multiple myeloma (MM), which are now being managed like chronic conditions. However, compared with other cancers, there is a lack of studies assessing adherence, health care resource utilization, and costs in patients with these cancers. OBJECTIVE: To assess factors associated with adherence to oral oncolytic therapies, health care utilization, and costs in patients with CLL/SLL or MM. METHODS: A retrospective database study was conducted using the IBM MarketScan Commercial Claims and Medicare Supplement databases. Adults (aged ≥ 18 years) diagnosed with and prescribed an oral oncolytic for CLL/SLL (ibrutinib or idelalisib) or MM (thalidomide, lenalidomide, or pomalidomide) between 2013 and 2016 and with continuous eligibility 6 months before and 12 months after oral oncolytic initiation were identified. Adherence to oral oncolytics was measured using the proportion of days covered (PDC) metric. Multiple linear regression and multivariable logistic regression were used to identify adherence predictors. Count models assessed the relationship between adherence and resource utilization, and generalized linear models assessed the relationship between adherence and health care costs. RESULTS: A total of 701 and 2,385 patients were identified with CLL/SLL or MM, respectively. Mean PDC (SD) for CLL/SLL and MM patients was 75.3 (22.5) and 57.6 (26.5), respectively. For CLL/SLL patients, those aged ≥ 65 years (beta [B] = -4.00) had lower medication use. Among MM patients, multiple predictors of higher medication use emerged: aged ≥ 65 years (B = 3.44), higher than average outpatient resource utilization (B = 3.53), insurance plan other than preferred provider organization (PPO; B = -2.58), previous cancer therapy (B = -2.81), higher number of concurrent unique therapeutic classes (B = -0.35), and higher comorbidity burden (B = -2.55). Patients with CLL/SLL and enrolled in plans other than a PPO were more likely to be adherent (OR = 1.41, 95% CI = 1.01-1.98), whereas patients who were aged ≥ 65 years, were residents of the southern United States, and had visited the emergency department in the baseline period were less likely to be adherent. For MM patients, those aged ≥ 65 years (OR = 1.68, 95% CI = 1.38-2.04) and with higher than average outpatient services utilization (OR = 1.24, 95% CI = 1.01-1.52) were more likely to be adherent, whereas those enrolled in plans other than a PPO, previously treated with cancer therapy, and with higher comorbidity burden were less likely to be adherent. In both cohorts, adherent patients had significantly lower odds of health care utilization and incurred lower medical costs, but higher prescription costs, following oncolytic initiation; however, total costs were not significantly lower in those adherent. CONCLUSIONS: Factors were identified that influenced adherence at the patient, treatment, and health system levels. These factors can be used to identify patients requiring interventions for improving medication-taking behavior and associated health care burden. DISCLOSURES: This study received no outside funding. Dashputre was recently employed by Novartis; K. Gatwood has received speaker fees from Jazz Pharmaceuticals; and J. Gatwood has received research funding from Merck & Co. and GlaxoSmithKline, unrelated to this study..

Impact of oral oncolytic initiation on medication adherence for pre-existing comorbid chronic conditions.

PURPOSE: Oral oncolytics have improved survival in hematological cancers like chronic myeloid leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and multiple myeloma; however, it is unclear of the extent to which initiating these treatments might impact adherence to oral therapies for pre-existing comorbid chronic conditions. METHODS: Adults diagnosed with and prescribed oral oncolytics for chronic myeloid leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, or multiple myeloma between 2013 and 2016 and with continuous eligibility six months before and after oral oncolytic initiation were identified from the Truven Health MarketScan databases. Among those identified, patients with pre-existing diabetes, hypertension, and/or hyperlipidemia with ≥1 fill for oral comorbid therapies were selected. Adherence to oral oncolytics and comorbid therapies was measured using the proportion of days covered metric. Wilcoxon signed-rank tests assessed changes in adherence for comorbid therapies after initiation of an oral oncolytic. Unadjusted difference-in-difference models assessed the impact of adherence to oral oncolytics on changes in adherence to comorbid therapies. RESULTS: Significant reductions in adherence after oncolytic initiation were observed across the comorbid therapies and were highest for patients taking lipid-lower agents (10.7-15.6%). Unadjusted difference-in-difference models revealed consistent and significantly lower reductions in adherence for those taking antihypertensives (chronic myeloid leukemia: p = 0.03; chronic lymphocytic leukemia/small lymphocytic lymphoma: p = 0.007; multiple myeloma: p = 0.09) and adherent to oral oncolytics. CONCLUSION: Initiation of oral oncolytics may negatively impact adherence to oral therapies for chronic comorbid conditions, necessitating the need for medication management strategies to help patients adhere to their entire medication regimen.

A Systematic Review of the Effect of Cancer Treatment on Work Productivity of Patients and Caregivers.

BACKGROUND: Cancer is a leading cause of death with substantial financial costs. While significant data exist on the economic burden of care, less is known about the indirect costs of treatment and, specifically, the effect on work productivity of patients and their caregivers. To examine the full effect of cancer and the potential value of new therapies, all aspects of care, including indirect costs and patient-reported outcomes, should be evaluated. OBJECTIVE: To perform a systematic review of the literature examining the effect of cancer treatment on work productivity in patients and their caregivers. METHODS: Articles, abstracts, and bibliographies were searched in MEDLINE, Cochrane, Scopus, CINAHL, and conference lists from the American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Academy of Managed Care Pharmacy up to January 2016. The PRISMA guidelines were used. Controlled search terminology included individual pharmacologic therapies for cancer and terms related to patient and caregiver work productivity. Citations were included if they evaluated the effect of cancer treatment on work productivity, used and described productivity assessments and instruments, and were written in English. Studies that reported only clinical outcomes or assessed only nonpharmacological treatments were excluded. Identified studies were screened and extracted for study inclusion by 2 independent reviewers, with adjudication by 2 secondary reviewers during the final eligibility phase. RESULTS: Of 978 potential citations, 62 articles or abstracts were included. Forty-six studies (74.2%) evaluated patient-related productivity; 10 studies (16.1%) focused on caregivers, and 6 studies (9.7%) were a combination. Sixteen countries contributed literature, including 26 studies (41.2%) conducted in the United States. The most commonly studied cancer was breast cancer (53.2%). Nearly 22% of the studies were conducted on multiple types of cancer. The significant diversity of study methodologies and measurements rendered a single unifying conclusion difficult. A variety of metrics were used to quantify productivity (hours lost, return to work, change of status, and activity impairment). The Work Productivity and Activity Impairment questionnaire was the most commonly used standardized tool (n = 9; 14.5%). Factors found to be associated with impairment in productivity included disease- and treatment-related effects, such as disease progression and severity, cognitive and neurological impairments, poor physical and psychological status, receipt of chemotherapy, and time and expenses required to receive therapy. CONCLUSIONS: This review highlights the considerable variety of studies that have assessed work productivity for cancer treatment and the multifaceted reasons affecting patients and caregivers. With increasing emphasis being given to understanding the value that patients assign to various aspects of cancer treatment, more streamlined information on productivity may be important to patients as they play a greater role in selecting treatment goals through shared decision making with their providers. DISCLOSURES: This study was funded by Novartis Pharmaceuticals, which provided the concept, general oversight, and research collaboration on the project. Covvey and Kamal received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists. Zacker is employed by, and owns stock in, Novartis Pharmaceuticals. A related poster abstract was presented at the Academy of Managed Care Pharmacy April 2016 Annual Meeting and published as Kamal KM, Covvey JR, Dashputre A, Ghosh S, Zacker C. A conceptual framework for valuebased oncology treatment: a societal perspective. J Manag Care Spec Pharm. 2016;22(4 Suppl A):S28. A publication-only abstract was presented at the American Society of Clinical Oncology 2016 Annual Meeting and published as Covvey JR, Kamal KM, Dashputre A, Ghosh S, Zacker C. The impact of cancer treatment on work productivity of patients and caregivers: a systematic review of the evidence. J Clin Oncol. 2016;34(Suppl):e18249. Study concept and design were contributed by Zacker, Kamal, and Covvey. Dashputre and Ghosh took the lead in data collection, along with Kamal and Covvey, and data interpretation was performed primarily by Shah and Bhosle, along with Ghosh, Dashputre, Covvey, and Kamal. The manuscript was written by Kamal, Covvey, Shah, and Bhosle and revised primarily by Zacker, along with Shah, Bhosle, Kamal, and Covvey.