A phase 3b, multicenter, open-label, single-arm study of roxadustat within a US dialysis organization: The DENALI study.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in-center or home dialysis. METHODS: Eligible patients received open-label roxadustat, dosed three times weekly for 24 weeks, with an optional extension of ≤1 year. Initial dosing depended on erythropoiesis-stimulating agent (ESA) dose at screening for patients receiving ESAs (≥6 weeks) and weight-based for those not (total <6 weeks). Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed. FINDINGS: Of 281 patients screened, 203 were treated and 201 included in the full analysis set. Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period. Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis. Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24. Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL. Prespecified subgroup analyses were consistent with primary analyses. Dosing adherence was 94%. Overall, 3.0% of patients received a red blood cell transfusion at up to Week 24. TEAEs and TESAEs were reported by 71.4% and 25.6% of patients, respectively. The most frequently reported TESAEs were COVID-19 (n = 5; 2.5%), and acute myocardial infarction, pneumonia, and sepsis (each n = 4; 2.0%). DISCUSSION: Roxadustat effectively achieved and/or maintained mean Hb levels ≥10.0 g/dL in patients receiving dialysis. The feasibility of incorporating oral roxadustat into dialysis organizations was successfully demonstrated with high dosing adherence. No new safety signals were identified.

A phase 3b, multicenter, open-label, single-arm study of roxadustat (ASPEN): Operational learnings within United States dialysis organizations.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations. METHODS: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed. FINDINGS: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%). DISCUSSION: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations.

Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors Secondary to Hyperkalemia Translates into Higher Cardiorenal Outcomes.

INTRODUCTION: Discontinuation of renin-angiotensin-aldosterone system inhibitor (RAASi) is common after hyperkalemia. We evaluated the risk of kidney and mortality outcomes associated with RAASi discontinuation among patients with chronic kidney disease (CKD) and hyperkalemia. METHODS: We identified adult patients with CKD (eGFR <60 mL/min/1.73 m2) who experienced new-onset hyperkalemia (potassium ≥5.0 mEq/L) between 2016 and 2017 from Kaiser Permanente Southern California and followed them through 2019. We defined treatment discontinuation as having ≥90-day gap in refills of all RAASi within 3 months after hyperkalemia. We used multivariable Cox proportional hazards models to evaluate the association between RAASi discontinuation and the primary composite outcome of kidney (≥40% eGFR decline, dialysis, kidney transplant) or all-cause mortality. We evaluated cardiovascular events and recurrence of hyperkalemia as secondary outcomes. RESULTS: Among 5,728 patients (mean age 76 years), 13.5% discontinued RAASi within 3 months after new-onset hyperkalemia. During the median 2 years of follow-up, 29.7% had the primary composite outcome (15.5% with ≥40% eGFR decline, 2.8% dialysis or kidney transplant, 18.4% all-cause mortality). Patients who discontinued RAASi had a higher all-cause mortality compared with those who continued RAASi (26.7% vs. 17.1%) but had no differences in kidney outcomes, cardiovascular events, and recurrence of hyperkalemia. RAASi discontinuation was associated with a higher risk of kidney or all-cause mortality composite outcome (adjusted hazard ratio [aHR] 1.21, 95% CI: 1.06, 1.37) mainly driven by all-cause mortality (aHR: 1.34, 95% CI: 1.14, 1.56). CONCLUSION: RAASi discontinuation after hyperkalemia was associated with worsened mortality, which may underscore the benefits of continuing RAASi among patients with CKD.

Real-World Modifications of Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Hyperkalemia Initiating Sodium Zirconium Cyclosilicate Therapy: The OPTIMIZE I Study.

INTRODUCTION: Hyperkalemia (HK) may result in disruptions of guidelines-concordant renin-angiotensin-aldosterone system inhibitors (RAASi), a standard of care in persons with chronic kidney disease (CKD). Such disruptions-dose reduction or discontinuation-diminish the benefits of RAASi, placing patients at risk of serious events and renal dysfunction. This real-world study evaluated RAASi modifications among patients who initiated sodium zirconium cyclosilicate (SZC) for HK. METHODS: Adults (≥ 18 years) initiating outpatient SZC (index date) while on RAASi were identified from a large US claims database (January 2018-June 2020). RAASi optimization (maintain same or up-titration of RAASi dosage), non-optimization (down-titration of RAASi dosage or discontinuation), and persistence were descriptively summarized following index. Predictors of RAASi optimization were assessed using multivariable logistic regression models. Analyses were conducted by subgroups, including patients without end-stage kidney disease (ESKD), with CKD, and with CKD + diabetes. RESULTS: A total of 589 patients initiated SZC during RAASi therapy (mean age 61.0 years, 65.2% male), and 82.7% patients (n = 487) kept RAASi after index (mean follow-up = 8.1 months). Most patients (77.4%) optimized RAASi therapy after initiating SZC; 69.6% maintained the same dosage while 7.8% had up-titrations. A similar rate of RAASi optimization was observed among subgroups without ESKD (78.4%), with CKD (78.9%), and with CKD + diabetes (78.1%). At 1-year post-index, 73.9% of all patients who optimized RAASi were still on therapy, while only 17.9% of patients who did not optimize therapy were still on a RAASi. Among all patients, predictors of RAASi optimization included fewer prior hospitalizations (odds ratio = 0.79, 95% CI [0.63-1.00]; p < 0.05) and fewer prior emergency department (ED) visits (0.78 [0.63-0.96]; p < 0.05). CONCLUSION: Consistent with clinical trial findings, nearly 80% of patients who initiated SZC for HK optimized their RAASi therapy. Patients may require long-term SZC therapy to encourage continuation of RAASi therapy especially after inpatient and ED visits.