Conversion From Erythropoiesis Stimulating Agents to Monthly C.E.R.A.
Conversion From Erythropoiesis Stimulating Agents to Monthly C.E.R.A.
Aims: To analyse the impact of dosing decisions for continuous erythropoietin receptor activator (C.E.R.A.), a continuous erythropoietin receptor activator.
Methods: This was a prospective, multicentre, single-arm study in haemodialysis patients receiving epoetin alfa/beta or darbepoetin alfa. After a 2-month screening phase, patients were converted to monthly C.E.R.A. using pre-filled syringes during a 5-month titration phase and a 2-month evaluation phase.
Results: Four hundred and twenty-four eligible patients were converted to C.E.R.A. Mean Hb were 11.7 ± 0.7, 11.7 ± 0.8 and 11.5 ± 0.8 g/dl during screening, titration and evaluation, respectively. C.E.R.A. starting dose was 125 μg (n = 311) or 200 μg (n = 106), with corresponding final doses of 129 ± 61 μg and 203 ± 58 μg. The mean number of C.E.R.A. dose decreases and increases were 0.9 ± 1.0 and 1.1 ± 1.0 per patient, respectively. Hb rarely exceeded 12.5 g/dl after a C.E.R.A. dose increase (< 8%) and remained ≥ 11 g/dl after a dose reduction on approximately three-quarters of occasions. Among the 53 occasions where Hb decreased ≥ 2 g/dl between two consecutive visits, the previous dose had been withheld (n = 9), concomitant blood loss, coagulopathy or infection was present (n = 13), or iron parameters were low (n = 17). There were 104 adverse events/month during screening, and 45/month during the titration/evaluation phases. Serious adverse events occurred in 18.0 and 21.0 patients/month during the screening and titration/evaluation phases, respectively.
Conclusion: Switching haemodialysis patients from shorter-acting ESA to once-monthly C.E.R.A. using pre-filled syringes is straightforward, and Hb levels remain stable. Starting dose recommendations and dose changes correlated well with the clinical setting. Collateral factors such as infection or aggravating concomitant medical conditions should be taken into account.
Erythropoiesis stimulating agents (ESA) are widely used to correct renal anaemia in the dialysis population, yet it is estimated that fewer than half of all patients on dialysis maintain haemoglobin (Hb) levels within the desired range of 11–12 g/dl over a 6-month period. One major barrier to establishing effective control is that fluctuations in Hb concentration are almost universal in haemodialysis patients under contemporary ESA therapy. Various factors contribute to this 'cycling', including administration of intravenous iron, concomitant illnesses or infections and chronic inflammation. The underlying cause, however, is the short, intermittent bursts of erythropoietic activity that are triggered by frequent ESA dosing, in contrast to the endogenous, more continuous release of erythropoeitin that occurs in response to physiological requirements in the healthy individual.
Use of longer-acting ESA therapy may help to reduce Hb cycling. However, extended dosing intervals using conventional ESAs can be problematic in clinical practice, and the National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) guidelines state that the efficacy of epoetin alfa and beta decreases if administered only once a week. Continuous erythropoietin receptor activator (C.E.R.A.), has a half-life of approximately 130 h compared with ≤ 9 h for epoetin alfa and beta and ~25 h for darbepoetin alfa. In addition, C.E.R.A. has a relatively low binding affinity for the erythropoietin receptor and slow systemic clearance, such that it provides continuous stimulation of erythropoiesis with a delayed peak reticulocyte count (at approximately day 8 post-dosing). As a result, efficacy is similar using C.E.R.A. once a month or multiple administrations of shorter-acting ESA agents in maintenance dialysis patients.
There are currently few published data regarding the practicalities of making monthly dose adjustments, for example in a patient with a rising Hb level. Furthermore, pre-filled syringes for C.E.R.A. have become available that were not used in the registration trials. The MIRACEL study was undertaken to examine the conversion of dialysis patients with chronic kidney disease (CKD) stage from short-acting ESAs to once-monthly C.E.R.A. therapy using pre-filled syringes. The experience from this large national trial may help to facilitate dosing decisions and management of haemodialysis patients receiving C.E.R.A. Herein, we describe C.E.R.A. doses and dose modifications, and individual responses to therapy, in the MIRACEL study population.
Abstract and Introduction
Abstract
Aims: To analyse the impact of dosing decisions for continuous erythropoietin receptor activator (C.E.R.A.), a continuous erythropoietin receptor activator.
Methods: This was a prospective, multicentre, single-arm study in haemodialysis patients receiving epoetin alfa/beta or darbepoetin alfa. After a 2-month screening phase, patients were converted to monthly C.E.R.A. using pre-filled syringes during a 5-month titration phase and a 2-month evaluation phase.
Results: Four hundred and twenty-four eligible patients were converted to C.E.R.A. Mean Hb were 11.7 ± 0.7, 11.7 ± 0.8 and 11.5 ± 0.8 g/dl during screening, titration and evaluation, respectively. C.E.R.A. starting dose was 125 μg (n = 311) or 200 μg (n = 106), with corresponding final doses of 129 ± 61 μg and 203 ± 58 μg. The mean number of C.E.R.A. dose decreases and increases were 0.9 ± 1.0 and 1.1 ± 1.0 per patient, respectively. Hb rarely exceeded 12.5 g/dl after a C.E.R.A. dose increase (< 8%) and remained ≥ 11 g/dl after a dose reduction on approximately three-quarters of occasions. Among the 53 occasions where Hb decreased ≥ 2 g/dl between two consecutive visits, the previous dose had been withheld (n = 9), concomitant blood loss, coagulopathy or infection was present (n = 13), or iron parameters were low (n = 17). There were 104 adverse events/month during screening, and 45/month during the titration/evaluation phases. Serious adverse events occurred in 18.0 and 21.0 patients/month during the screening and titration/evaluation phases, respectively.
Conclusion: Switching haemodialysis patients from shorter-acting ESA to once-monthly C.E.R.A. using pre-filled syringes is straightforward, and Hb levels remain stable. Starting dose recommendations and dose changes correlated well with the clinical setting. Collateral factors such as infection or aggravating concomitant medical conditions should be taken into account.
Introduction
Erythropoiesis stimulating agents (ESA) are widely used to correct renal anaemia in the dialysis population, yet it is estimated that fewer than half of all patients on dialysis maintain haemoglobin (Hb) levels within the desired range of 11–12 g/dl over a 6-month period. One major barrier to establishing effective control is that fluctuations in Hb concentration are almost universal in haemodialysis patients under contemporary ESA therapy. Various factors contribute to this 'cycling', including administration of intravenous iron, concomitant illnesses or infections and chronic inflammation. The underlying cause, however, is the short, intermittent bursts of erythropoietic activity that are triggered by frequent ESA dosing, in contrast to the endogenous, more continuous release of erythropoeitin that occurs in response to physiological requirements in the healthy individual.
Use of longer-acting ESA therapy may help to reduce Hb cycling. However, extended dosing intervals using conventional ESAs can be problematic in clinical practice, and the National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) guidelines state that the efficacy of epoetin alfa and beta decreases if administered only once a week. Continuous erythropoietin receptor activator (C.E.R.A.), has a half-life of approximately 130 h compared with ≤ 9 h for epoetin alfa and beta and ~25 h for darbepoetin alfa. In addition, C.E.R.A. has a relatively low binding affinity for the erythropoietin receptor and slow systemic clearance, such that it provides continuous stimulation of erythropoiesis with a delayed peak reticulocyte count (at approximately day 8 post-dosing). As a result, efficacy is similar using C.E.R.A. once a month or multiple administrations of shorter-acting ESA agents in maintenance dialysis patients.
There are currently few published data regarding the practicalities of making monthly dose adjustments, for example in a patient with a rising Hb level. Furthermore, pre-filled syringes for C.E.R.A. have become available that were not used in the registration trials. The MIRACEL study was undertaken to examine the conversion of dialysis patients with chronic kidney disease (CKD) stage from short-acting ESAs to once-monthly C.E.R.A. therapy using pre-filled syringes. The experience from this large national trial may help to facilitate dosing decisions and management of haemodialysis patients receiving C.E.R.A. Herein, we describe C.E.R.A. doses and dose modifications, and individual responses to therapy, in the MIRACEL study population.