Disclosures: Chatoth, Hymes, Maddux and Stennett report they have shareholdings/options in Fresenius Medical Care. Pecoits-Filho reports he is employed by Arbor Research Collaborative for Health and receives research grants, consulting fees and honoraria from AstraZeneca, Novo Nordisc, Akebia Therapeutics and Fresenius Medical Care. Maddux reports he has directorships in the Fresenius Medical Care management board, Goldfinch Bio and Vifor Fresenius Medical Care Renal Pharma.
September 10, 2020
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Provider evaluates methoxy polyethylene glycol-epoetin beta in peritoneal dialysis

Disclosures: Chatoth, Hymes, Maddux and Stennett report they have shareholdings/options in Fresenius Medical Care. Pecoits-Filho reports he is employed by Arbor Research Collaborative for Health and receives research grants, consulting fees and honoraria from AstraZeneca, Novo Nordisc, Akebia Therapeutics and Fresenius Medical Care. Maddux reports he has directorships in the Fresenius Medical Care management board, Goldfinch Bio and Vifor Fresenius Medical Care Renal Pharma.
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There are more than 700,000 prevalent cases of end-stage kidney disease in the United States, which is increasing by approximately 20,000 cases per year.1

Peritoneal dialysis is a home renal replacement modality used by about 10% of prevalent patients with ESKD.2

Home dialysis use continues to increase due to the potential for better clinical outcomes, a concerted effort by the industry to educate patients and physicians, and the 2019 presidential executive order launching Advancing American Kidney Health.3

Home therapies are cost-effective alternatives to in-center dialysis. These have been shown to improve outcomes reported by patients and yield higher patient autonomy.4 The current COVID-19 pandemic makes dialysis care in the home setting favorable with less frequent clinic visits.5 The shift of renal replacement therapy (RRT) from in-center hemodialysis to a home dialysis modality may improve the quality and quantity of life in patients with ESKD,6 yet presents a unique challenge to treating and managing complications of this disease.

Anemia management

Anemia due to erythropoietin deficiency is a common complication of kidney disease, present in more than 90% of patients undergoing dialysis.7 Anemia is primarily treated via erythropoiesis-stimulating agents (ESAs), with about 80% of patients on dialysis in the United States receiving an ESA therapy.8 Historically, short- and medium-acting ESAs (epoetin and darbepoetin) were used for the treatment of anemia in patients with chronic kidney disease. In 2007, a long-acting ESA (methoxy polyethylene glycol- epoetin beta) was approved by the FDA for use and this continuous erythropoiesis receptor activator (CERA) was introduced as an option in the United States in 2014.

A recent, randomized controlled trial that enrolled nearly 3,000 patients with ESKD, including patients on PD, showed once-monthly dosing of methoxy polyethylene glycol-epoetin beta is non-inferior to darbepoetin or epoetin regarding maintaining hemoglobin (Hgb) targets, cardiovascular outcomes and all-cause mortality.9

From 2015 to 2019, Fresenius Kidney Care converted patients on PD using short- and medium-acting ESAs to the long-acting ESA. The rationale for the conversion to CERA was to increase patient adherence to therapy while maintaining equivalent clinical outcomes. The objective of this analysis is to describe the practice patterns and achievement of CKD anemia targets observed during the conversion from short- and medium-acting ESAs to the long-acting ESA among patients on PD.

We included data from patients with ESKD who received PD for RRT for 3 months or more prior to, and 6 months or more after, conversion to CERA; received one or more doses of an ESA within 3 months prior to conversion to CERA; used the same ESA analog 3 months or more prior to conversion to CERA and only used the ESA analog of CERA 6 months or more after conversion. We restricted the analysis to include data from patients who completed the 6-month follow-up after conversion to CERA.

We evaluated the trends in anemia management 3 months before and 6 months after conversion to CERA. We considered variables for the average ESA and IV iron dose per patient per month (ppm), as well as the average monthly mean Hgb, transferrin saturation (TSAT) and ferritin levels. The dose for ESA analog types were converted to CERA-equivalents for a reference.

Figure 1: Shown is the monthly ESA dosing in patients on PD before and after conversion to CERA.

Source: Fresenius Kidney Care.

The location of the ESA administration was captured by groups of patients who were universally administered ESA in the dialysis clinic, universally self- administered their ESA doses at home or had a combination of both.

We tabulated patient characteristics using mean ± standard deviation (SD) for continuous variables, and counts/proportions for categorical variables. We calculated the average ESA and IV iron dose ppm from the total monthly dose administered and considered the proportion of patients per month on a dose hold. The average monthly values were computed for Hgb, ferritin and TSAT, and the proportion of patients achieving target ranges was assessed. The monthly timeframes were defined as 28-day periods before (-84 days) and after (+168 days) conversion to CERA.

The ESA conversion calculations from epoetin/darbepoetin to, and from, CERA are limited to the Mircera U.S. Prescribing Information, which recommends categorical ranges of ESA dose with the intent to titrate after initial dosing.10 While this conversion logic is valuable in a clinical approach, it does not allow for direct comparisons of equivalent ESA doses. Therefore, we calculated ESA dose ratios using data from the MIRCERA PASS randomized controlled trial that established the median weekly ESA dose for each analog during the first 7 years of follow-up.9 For each ESA analog, we calculated the monthly dose and the conversion ratio (Table 1). The CERA-equivalent dose was computed by dividing the ESA dose of epoetin/darbepoetin (numerator) by the ESA conversion rate (denominator). The CERA-equivalent doses were pooled for epoetin and darbepoetin accounting for the percentage of patients treated by each analog.

Results

We analyzed data from 5,577 patients on PD who transitioned from epoetin/darbepoetin to CERA and met eligibility criteria for this analysis. The mean age of patients was 56.4±15 years; 50.7% were women and 38% had diabetes (Table 2). On average, patients had a PD vintage of 23.7±17.1 months and an overall dialysis vintage of 34.8±33.7 months. Most patients (82.9%) were treated by continuous cycling PD, and a minority (10.2%) were treated by continuous ambulatory PD.

ESA dose and administration

Figure 2: Monthly IV iron dosing and hemoglobin and ferritin in patients on PD before and after conversion to CERA.

Source: Fresenius Kidney Care.

The ESA dose for both epoetin and darbepoetin had decreasing trends before conversion, and conversely, the proportion of patients on a dose hold (ESA dose=0) increased in the months before conversion to CERA. The overall average pooled CERA-equivalent ESA dose was only slightly lower (-4 g ppm) in the 6 months after compared to 3 months before conversion to CERA (Table 3; Figure 1). By design, during the first month of conversion (28 days), all patients were administered CERA (average dose=152 g ppm). The trend in CERA dose decreased in the months after conversion to qualitatively a lower relative dose than 3 months before conversion with epoetin. The proportion of patients on a dose hold was notably higher after switching to CERA. During the 6 months of follow-up, 72% of CERA doses were administered 21 days or more after the prior dose.

We further assessed the differences in ESA dosing not considering the transition period the month before and after conversion. The average pooled CERA-equivalent ESA dose was 17 g ppm higher before (123.2 g ppm) vs. after (105.9 g ppm) conversion to CERA (Table 3; Figure 1). Remarkably, there were more (28 percentage points) patients on a dose hold after conversion to CERA.

The location of ESA administration was clearly impacted by conversion to CERA. The change in exclusive ESA administrations given by a certified nurse in the clinic increased from 41% before to 98% after conversion to CERA, while home self- administrations decreased, respectively.

Iron dose, ferritin and Hgb

Overall, 25% to 28% of patients on PD received IV iron before and after conversion. There were small variations in IV iron dose before and after conversion to CERA (Figure 2) that were highest on the month of conversion; these minor variations appeared clinically unremarkable.

The average monthly Hgb levels were in the dialysis providers target range (10 g/dL to 11 g/dL) and relatively stable throughout the conversion from epoetin/darbepoetin to CERA (Figure 2). There was a slightly lower Hgb level (0.3 g/dL) the month of conversion compared to both the 28 days before and 28 days to 56 days after conversion to CERA.

The average monthly ferritin levels were in the dialysis providers target range (800 ng/mL to 1,200 ng/mL) during the analysis period. The average ferritin levels were observed to rise by 45 ng/mL across the 3 months before conversion to CERA and continued to progressively rise by an additional 74 ng/mL across the 6-month follow-up after conversion (Figure 2). Assessment of achieved ferritin targets identified decreasing trends in the proportion of patients with ferritin levels 100 ng/mL or more to less than 800 ng/mL and increasing trends in the percentage of patients with ferritin levels 800 ng/mL or more after conversion to CERA.

Average monthly TSAT levels remained in the dialysis providers target range (30% to 50%) before and after conversion ranging from 35% to 37%. Assessment of achieved TSAT targets showed similar percentage of patients in each category before and after conversion to CERA.

Discussion

The ESA conversion to CERA among a cohort of anemic patients on PD at a large integrated kidney disease health care company was qualitatively associated with a decrease in the mean ESA dose, a robust increase in the proportion of patients on an ESA dosing hold, and a change to primarily nursing assisted ESA administration in the outpatient clinic setting. The achievement of anemia targets was maintained throughout the conversion to CERA. For this analysis, we created a novel method to calculate equivalent doses to CERA from short- and medium-acting ESAs, which will be of importance for providers to estimate comparable doses between various ESA types.

Similar to our analysis, a study of 28 patients on PD from Japan found lower dose-equivalent requirements for patients converted from medium-acting (darbepoetin) to CERA (mean CERA-equivalent dose 118.5 g vs. CERA dose 89.9 g considering a dose conversion rate of 1.24) with additional cited effect of lower blood pressure with CERA (mean systolic blood pressure darbepoetin alfa 133.8 mmHg vs. CERA 129.5 mmHg).11 The suggested impact of ESA type on blood pressure control may be clinically important and warrants further investigation.

Unlike the study in Japan, most patients in our analysis were converted from a short-acting ESA (darbepoetin; n=308/5.5% vs. epoetin; n=5,269/94.5%) to CERA and we did not exclude patients currently on iron therapy. One interesting trend to note in our analysis is the small, yet not unremarkable rising ferritin level observed after conversion to CERA, while the dose of IV iron remains relatively stable.

In our analysis, we also found CERA was able to maintain anemia Hgb targets consistent with other studies in the PD population.12,13 We found most of our patients (about 70%) were administered CERA with a monthly regimen.

We developed logic to calculate equivalent doses for short-, medium- and long-acting ESAs, which were derived using data from the MIRCERA PASS study that included more than 2,800 patients randomized to CERA or reference ESA with a median follow-up period of 3.4 years.9 This logic can be considered for future investigations of ESA types in patients with ESKD.

Although this analysis has strengths using real world data from a national sample of patients on PD converted to CERA, there are some key limitations. This analysis may not be generalizable to the overall PD population given we included patients who were anemic receiving routine ESA treatment (94.5% epoetin and 6% darbepoetin before conversion) and remained exclusively for 6 months on PD therapy without any technique failure events.

Conclusions

Conversion to CERA in patients on PD for the treatment of anemia appears to associate with a lower relative ESA requirement (a lower ESA dose and a higher proportion of patients on an ESA dose hold) and more patients having nurse-assisted administration at routine clinic visits, while maintaining laboratory targets. These favorable attributes found with the conversion to CERA appear to suggest it could be a suitable option for anemia management in this population.