An observational study of the effectiveness of darbepoetin administered in dialysis patients once every 2 weeks for 12 months

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1 Clinical Nephrology, Vol. 75 No. 3/2011 ( ) An observational study of the effectiveness of darbepoetin administered in dialysis patients once every 2 weeks for 12 months Original 2011 Dustri-Verlag Dr. K. Feistle ISSN DOI /CN J.B. Rottembourg 1, I. Bridges 2, W. Pronai 3, M. Feriani 4, L.P. McMahon 5, J.M.J. De Meester 6, M. Farouk 7 and B. Molemans 7 1 Centre Suzanne Levy, Diaverum Group, Clinique du Mont Louis, Paris, France, 2 Amgen Ltd., Cambridge, UK, 3 Barmherzige Brüder Eisenstadt, Eisenstadt, Austria, 4 Ospedale dell Angelo, Via Pacagnella, Mestre, Italy, 5 Eastern Health, Melbourne, Australia, 6 AZ Nikolaas, Sint-Niklaas, Belgium, and 7 Amgen (Europe) GmbH, Zug, Switzerland Darbepoetin Q2W in dialysis patients Key words anemia darbepoetin dialysis hemoglobin observational study Received March 22, 2010; accepted in revised form October 28, 2010 Correspondence to J.B. Rottembourg, MD Centre Suzanne LEVY, Diaverum Group, Clinique du Mont Louis, 8 rue de la Folie Regnault, Paris, France jacques.rottembourg@ wanadoo.fr Abstract. Aims: Erythropoiesis-stimulating agents (ESAs) are recommended for managing renal anemia. ALTERNATE is an observational study in European and Australian dialysis patients evaluating darbepoetin (DA) once every 2 weeks (Q2W) in clinical practice. Methods: Adult dialysis patients initiating treatment with DA Q2W were eligible regardless of previous/current ESA use. Data were collected 6 months before and 12 months after Q2W initiation. The primary endpoint was hemoglobin (Hb) concentration 12 months after initiation. Results: A total of 6,112 patients were enrolled; 6,104 were eligible (87% hemodialysis, 12% peritoneal dialysis). Before initiation, 77.3%, 8.8%, and 7.8% of patients were receiving DA, epoetin, and epoetin, respectively; 6% were ESA naïve. Mean (95% CI) Hb (g/dl) was ( ) 6 months before initiation, ( ) at initiation, and ( ) 12 months after initiation. Geometric mean (95% CI) weekly ESA dose (µg/wk) was ( ) immediately before initiation, ( ) at initiation, and ( ) 12 months after initiation. At month 12, 77.3% of patients were receiving DA Q2W. Conclusions: This large observational study demonstrates that Hb concentrations can be effectively maintained over 12 months in a general dialysis population with DA Q2W without an increase in ESA dose. Introduction Anemia has been recognized as an important consequence of chronic kidney disease that occurs in almost all dialysis patients and causes loss of physical and functional capabilities. Correcting hemoglobin (Hb) helps to improve quality of life in patients with renal anemia undergoing dialysis [1, 2], although normalizing Hb in such patients provides little or no improvement in survival and may cause harm [3]. The European Best Practice Guidelines (EBPGs) [4], more recent position statement from European Renal Best Practice [5] and guidelines of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [6] recommend erythropoiesisstimulating agents (ESAs) to partially correct and maintain Hb concentrations in dialysis patients. However, it can be challenging to achieve the target ranges suggested by these guidelines, as intercurrent events are common and can affect response to ESA treatment [7, 8], making it difficult to control Hb levels. Darbepoetin (DA) has an approximately threefold longer half-life and greater in vivo biological activity than recombinant human erythropoietin and an early study in hemodialysis (HD) patients showed that intravenous (IV) DA was safe and effective for treating anemia on a once-weekly (QW) dosing schedule [9, 10]. Although the larger and more recent TREAT trial demonstrated risks associated with ESA treatment [11], this was conducted in diabetic patients with higher baseline Hb levels who were not undergoing dialysis and ESA treatment was used to normalize, rather than partially correct, Hb. Trials in selected HD and peritoneal dialysis (PD) patients demonstrated that extending DA dosing schedules to once every 2 weeks (Q2W) yielded comparable efficacy to QW

2 Darbepoetin Q2W in dialysis patients 243 dosing with respect to Hb concentrations [12, 13, 14]. The option of a Q2W dosing schedule for patients who do not require QW dosing may offer efficiencies in time and cost for providers at dialysis centers [15, 16, 17, 18], and potentially reduce risk of needle stick injury, dosing errors, and waste [16, 17]. The ALTERNATE study (A Long Term Non-interventional Study to Evaluate the Effectiveness of Aranesp in Dialysis Patients when Administered Once Every Two-Weeks) was designed to assess Hb concentration in European and Australian dialysis patients 12 months after initiation of DA Q2W IV or subcutaneous (SC), thus providing a more comprehensive understanding of DA Q2W use in clinical practice. Here, we provide the results for the overall study population. Subjects and methods Study design ALTERNATE was an observational, longitudinal, non-interventional, multicenter study in a general dialysis population, with a duration of 18 months. Adult ( 18 years) HD and PD patients initiating DA Q2W in August 2004 or later were eligible for enrollment regardless of previous/current ESA use. The last patient completed the study by September Patients were excluded if they had received DA in an interventional study in the 6 months before converting to DA Q2W, were receiving investigational agents, or had clinical evidence of current malignancy except for basal cell or squamous cell carcinoma of the skin and cervical intraepithelial neoplasia. Patients were treated according to routine clinical practice in the respective treatment center. Where required by local law, the study protocol and informed consent materials were approved by the local independent ethics committee, and patients provided written informed consent prior to study entry. Data collection Data were collected from 344 centers from Australia, Austria, Belgium, Czech Republic, Denmark, Finland, France, Hungary, Italy, Ireland, Netherlands, Norway, Portugal, Poland, Slovenia, Sweden, and the United Kingdom, across different-sized centers, either academic or non-academic. To avoid centers with minimal use of DA Q2W, each center was required to have treated 10 dialysis patients with DA Q2W by the time of inclusion in the study. Sequential enrollment occurred until the target number of patients was reached. Data were abstracted retrospectively from patient charts for up to 6 months before initiation of DA Q2W, and retrospectively and/or prospectively for up to 12 months after initiation. The proportion of retrospective or prospective data was dependent on when the patient enrolled in the study relative to their date of initiation of DA Q2W. The duration of retrospective data collection was < 3 months for 65% of patients, 3 months for 34.3%, and unknown for 0.7%. Study endpoints The primary endpoint was the Hb concentration 12 months after initiation of DA Q2W. Secondary endpoints included Hb concentration each month; the proportion of patients with Hb > 11 g/dl (i.e., EBPG treatment target [4]) each month during the study; patient demographics and characteristics; ESA utilization (e.g., ESA dose, dose changes); iron usage and outcomes; and the incidence of adverse drug reactions attributable to DA(DA-ADRs). Statistical methods Sample size calculations were based on the number of patients needed to represent a heterogeneous dialysis population for specific patient subsets to allow calculation of mean Hb concentration 12 months after initiation of DA Q2W with adequate precision (width of 95% confidence interval (CI) approximately 0.4 g/dl) and assuming a standard deviation (SD) of 1.8 g/dl. The smallest patient subset to be studied was expected to be at least 5% of the total study population. Based on these assumptions, it was estimated a minimum of 312 patients would be required for each subset, and a sample size of approximately 6,000 patients was required [19].

3 Rottembourg, Bridges, Pronai et al. 244 Figure 1. Patient disposition. Figure 2. A: Mean (95% CI) Hb (g/dl) and ESA dose (µg/wk) by month for the FAS as observed (n = 6,104) over 18 months. B: An expanded view of the ESA dose at the time of initiation of DA Q2W. [I] = at initiation of DA Q2W. a Hb concentration: Hb each month was defined as the single closest value in a ± 2 week analysis window; at initiation, it was the single closest value in a 8 week analysis window; b weekly dose: average dose received over each month; each dosing frequency (e.g., TIW, BIW, QW, Q2W) was converted to a corresponding daily dose and then a weekly equivalent; Day 1 was the dose of the regimen applicable the day before initiation (converted to a weekly equivalent); Day +1 (initiation) was the first dose of DAQ2W (converted to a weekly equivalent); c No imputation for missing values; FAS = full analysis set. Descriptive analyses were performed on the study data using the full analysis set (FAS), which included all patients eligible for the study (Figure 1). Continuous variables are described using mean, SD, and 2-sided 95% CIs. For categorical variables, the number and percentage of participants were reported. Endpoints were analyzed with the FAS as observed (no imputation for missing values) unless noted otherwise. Additional analyses were conducted to examine the effect of patient withdrawal or missing data on Hb concentration, including FAS with last observation carried forward (LOCF), which imputed data from the previous observation for missing values, although cross-over of data from before to after initiation was not permitted. All statistical analyses were performed using SAS/STAT software (version 8.2, SAS Institute Inc., Carey, NC, USA). Analysis of monthly Hb was based on the value closest in time to the date of the scheduled time point (e.g., 1, 2, or 3 months) and which fell within a ± 2-week window. An exception was made for the time point of Q2W initiation to ensure the maximum number of patients for evaluation; the analysis of Hb was based on the value closest in time to the date of initiation, but could include values up to 8 weeks before. 90% of the Hb data fell within 4 weeks of DA Q2W initiation. ESA doses were summarized as geometric means (log transformation of the data) to reduce the impact of non-normal data distribution on the arithmetic mean dose. Epoetin doses were converted from IU to µg using European (200 : 1) or Australian (200 : 1 SC or 240 : 1 IV) product label guidelines. The weekly ESA dose was calculated for individual patients for each month using all available dosing data within that month (30 days). Each dosing frequency was converted to a corresponding daily dose. The daily dose applicable for a month was the average of the daily doses for all days within that month, then normalized to a weekly equivalent by multiplying by 7. Results A total of 6,112 patients were enrolled; 6,104 eligible patients were included in the FAS (92.8% from Europe and 7.2% from

4 Darbepoetin Q2W in dialysis patients 245 Table 1. Patient characteristics at the time of initiation of darbepoetin Q2W. Hb and ESA Dose Characteristic n = 6,104 Age, mean ± SD, years 63.9 ±15.3 Sex, n (%) Male 3,575 (58.6) Female 2,507 (41.0) Not recorded 22 (0.4) Dialysis modality Hemodialysis 5,318 (87.1) Peritoneal dialysis 741 (12.1) Not recorded 45 (0.7) Time since initiation of dialysis, mean ± SD, years 5.0 ± 5.3 Primary etiology of CKD, n (%) Glomerulonephritis 1,173 (19.2) Diabetes mellitus 1,162 (19.0) Hypertension 1,144 (18.7) Unknown 781 (12.8) Interstitial nephropathy/obstructive nephropathy 644 (10.6) Polycystic kidney/hereditary disease 493 (8.1) Tumors 59 (1.0) Other 647 (10.6) Not recorded 1 (< 0.1) History of cardiovascular disease, n (%) Yes 3,462 (56.7) No 2,497 (40.9) Unknown/not recorded 145 (2.4) History of diabetes mellitus, n (%) Yes 1,693 (27.7) Type I 251 (4.1) Type II 1,408 (23.1) Type not specified 34 (0.6) No 4,352 (71.3) Unknown/not recorded 59 (1.0) Previous kidney transplant, n (%) Yes 635 (10.4) No 5,423 (88.8) Not recorded 46 (0.8) CKD = chronic kidney disease; SD = standard deviation. Australia) and 5,116 (83.8%) patients completed the study (Figure 1). At initiation of DA Q2W, the mean age was 63.9 years, 58.6% of patients were male (Table 1), and 87.1% of patients were undergoing HD and 12.1% PD. For HD patients, vascular access was native arteriovenous fistula in 80.8% of patients, synthetic graft in 6.0%, and other types of access in 12.5%. The primary endpoint of mean (95% CI) Hb concentration 12 months after initiation of DA Q2W was g/dl ( ) in the FAS using the data as observed. This is comparable to the mean of g/dl (95% CI, ) in the FAS-LOCF analysis. For consistency with the dose, Hb results based on the FAS as observed are presented hereinafter. Figure 2 shows Hb concentrations and ESA dose during the study. The mean (95% CI) monthly Hb concentration at 6 months prior to initiation ( 6 months) was g/dl ( ) and at initiation was g/dl ( ). The proportion of patients with Hb > 11 g/dl was 69.4% (2,689/3,874) at 6 months, 75.7% (4,496/ 5,939) at initiation, and 69.0% (2,949/4,276) at 12 months. Of the 5,972 patients (98%) for whom full data were available following initiation of Q2W dosing, 3,390 (57%) maintained Hb concentration within a 2-g/dl range in the 12 months following initiation. There was a steady decrease in the ESA dose over the 6 months before initiation; at initiation, a substantial drop in dose was observed (Figure 2). Patients initiated DA Q2W at a geometric mean (95% CI) dose of µg ( ); that is a weekly equivalent dose of µg/wk ( ), which is a reduction from the regimen received immediately before DA Q2W initiation (27.27 µg/wk ( )). From initiation to 12 months, the ESA dose appeared to steadily increase, although it remained lower than the ESA dose just prior to initiation. At month 12, the geometric mean ESA dose was µg/wk ( ). When dose was adjusted for weight, geometric mean dose was µg/kg/wk ( ) at initiation of DA Q2W and µg/kg/wk ( ) at 12 months. Subgroup analyses were completed for dialysis modality, administration route in HD patients, and vascular access type in HD patients (Figure 3). In all subgroups, there is a similar pattern of change in both Hb (increase until initiation followed by return to a similar level by month 6) and dose (reduction immediately after initiation followed by an increase but not a return to pre-initiation level by Month 12). PD patients generally had a lower dose and slightly higher Hb than HD patients.

5 Rottembourg, Bridges, Pronai et al. 246 Figure 3. Mean (95% CI) Hb (g/dl) and ESA dose (µg/wk) by month for the FAS as observed over 18 months in patients undergoing A: hemodialysis and B: peritoneal dialysis; in hemodialysis patients receiving C: intravenous and D: subcutaneous darbepoetin ; and in hemodialysis patients with E: native fistula, F: synthetic graft, or G: other access. Note: route of ESA administration (Graphs C and D) was not the same before initiation and after initiation in all patients. Table 2. ESAdose changes before and after initiation of darbepoetin Q2W*. Before initiation Months 6 to 1 (n = 5,739) Months 1 to 6 (n = 6,100) After initiation Months 7 to 12 (n = 5,629) No change 2,864 (49.9) 2,601 (42.6) 2,537 (45.1) 1 2 changes 2,236 (39.0) 2,642 (43.3) 2,416 (42.9) 3 5 changes 584 (10.2) 791 (13.0) 609 (10.8) 6 changes 55 (1.0) 66 (1.1) 67 (1.2) *Number of patients (%). Hb was very similar for all vascular access methods, while dose was slightly higher for patients with access other than native fistula or synthetic graft. ESA treatment patterns Prior to initiation of DA Q2W (Figure 4A), most patients were receiving DA (77.3%; 4,718), the majority of whom were on QW dosing (93.5%; 4,412) and IV administration (77.8%; 3,669). The mean ± SD time

6 Darbepoetin Q2W in dialysis patients 247 Figure 4. ESA treatment characteristics A: immediately before and B: 12 months after initiation of darbepoetin Q2W. a ESA-naïve patients were excluded from calculations at Day 1; BIW = twice weekly; CI = confidence interval; ESA = erythropoiesis stimulating agent; IV = intravenous; Q2W = once every other week; QW = once weekly; QM = once monthly; SC = subcutaneous; TIW = thrice weekly. since starting any ESA treatment was 4.0 ± 3.1 years. Of patients, 6% (n = 366) were ESAnaïve before initiation. At initiation, 78.9% (4,817) and 21.1% (1,287) of the 6,104 patients were receiving DA Q2W via the IV and SC routes, respectively. The SC route was employed in 9.9% (528/5,318) of HD patients and 96.8% (717/741) of PD patients. Of the 4,412 patients who converted from DA QW to DA Q2W, 43% (1,914) maintained an equivalent weekly dose upon initiating DA Q2W, 6.9% (306) had an increase in dose, and 46.6% (2,055) had their doses reduced; 3.1% (136) had a dose of zero immediately prior to conversion, and < 1% (1) had an unknown dose. About 50% of patients required dose changes within a 6-month period over the course of the study, most of which involved one to two titrations (Table 2). At 12 months, most patients were receiving DA Q2W (77.3%) (Figure 4B). Hospitalizations During the 12 months after initiation, 2,612 patients (42.9%) experienced at least one hospitalization. The mean hospital stay for these patients (and not the entire population) was 16.9 days (median, 10.0 days). The

7 Rottembourg, Bridges, Pronai et al. 248 patients (7.1%) withdrew from the study due to death, but no fatal ADRs were recorded. Discussion Figure 5. Reason for hospitalization during the 12 months after initiation of darbepoetin Q2W (n = 2,612). reasons for hospitalization included electrolyte disorders (29.1%) and infection (23.3%); 50.8% of causes were recorded as other (Figure 5). Iron usage Iron usage remained stable over the course of the study. The proportion of patients receiving iron therapy ranged from 65.6% to 70.6% for each 3-month period before and after initiation of DA Q2W; most of these patients received IV iron (range %). The mean serum ferritin concentrations and transferrin saturation values for the 3-month periods were maintained at or above recommended targets [20] throughout the study (ranges µg/l and %, respectively). Adverse drug reactions The rate of DA-ADRs was low during the 12 months after initiation of DA Q2W, with no unexpected events emerging. A total of 16 non-serious DA-ADRs related to DA treatment were reported in 13 patients (0.2%): Hb increase (n = 6), myalgia (n = 2), arthralgia (n = 1), diarrhea (n = 1), Hb decrease (n = 1), hypertension (n = 1), SC injection site pain (n = 1), muscle weakness (n = 1), rash (n = 1), and thrombosis in device (n = 1). Atotal of 432 ALTERNATE is one of the few large, longitudinal, observational studies undertaken to examine the clinical use of ESAs in the European and Australian dialysis population. The data reported here demonstrate that in clinical practice and in a heterogenous dialysis population, Hb concentrations can be maintained in most patients using DA Q2W with no increase in ESA dose, regardless of previous ESA use, dialysis mode, or route of administration. It is notable that the ALTERNATE study population appeared to be biased toward patients with increasing Hb concentrations over the 6 months prior to initiation of DA Q2W. After initiation, and likely due in part to a dose reduction, Hb concentrations slightly decreased after 12 months to levels observed 6 months before initiation. Conversely, the weekly ESA dose gradually increased after initiation and at 12 months was comparable to the pre-initiation dose. A number of factors may have contributed to these observations. The trends in Hb concentration and ESA dose around the time of initiation may reflect a common practice pattern in Europe of switching patients on DA QW who tend to have rising Hb over a few months to DA Q2W without typically doubling their doses so that overall the dose is actually lowered (Figure 2B). More than half of the ALTERNATE patients appeared to fall into this practice pattern. Prior to initiation, 77% of patients had been receiving DA QW. In addition, Hb concentrations and ESA dosing may not have been stabilized in these patients before initiation of DA Q2W. Clinical trial selection criteria, on the other hand, often require stable Hb concentrations or ESA dose for a period of time prior to inclusion. It also should be acknowledged that during the course of this study, in early March 2008, a label change regarding the Hb target was required for ESA agents available in Europe. The recommended Hb target was changed from > 11 g/dl (with an individualized upper limit of < 14 g/dl) to a target of g/dl for all patients [21]. It is unlikely that the modifications to the label had a sig-

8 Darbepoetin Q2W in dialysis patients 249 nificant effect on the overall results. Data from 17.9% (1,093) of patients may have been affected by this label change, as their initiation of DA Q2W occurred between March and September This may in part explain why there was a small increase in the proportion of patients with Hb < 11 g/dl by the end of the study, given that the lower limit of the Hb target range was decreased to 10 g/dl. Hospitalizations were frequently reported in this study, as is expected with dialysis patients as CKD is a serious illness. Electrolyte disorders and infections were predominant diagnoses for hospitalizations (29% and 23%, respectively), indicating that these patients became seriously ill during the study period with interruption of their routine treatment, including anemia management. Changes in ESA use (type of agent, dose, or dosing schedule) may also have occurred either to ensure target Hb concentrations were maintained or because of institutional practices. The ALTERNATE data highlight the changes in dosing patterns in the clinical practice setting during the treatment of anemia. Most patients were on the DAQ2W regimen at month 12. However, for other patients, treatment appears to have been adjusted after initiation of Q2W. The DA-ADRs that emerged during AL- TERNATE were consistent with those reported in controlled trials of dialysis patients receiving DA [10, 12, 22, 23]. There were no reported cases of antibody-mediated pure red cell aplasia after initiation of DA Q2W. The rates of DA-ADRs during ALTERNATE appear to be lower than those observed in controlled trials of DA and may reflect underreporting [24]. Limitations of this study should be acknowledged. The ALTERNATE study was an observational study, and thus the generalizability of these results is dependent on the selection criteria for patients and centers. History of cardiovascular disease was noted as present or absent, but no details were collected. Adverse events were not recorded; ADRs were those reported by physicians (no adjudication), and may have been under-reported. Deaths were recorded only where these were the reason for discontinuation from the study; deaths following withdrawal were not recorded. No details of the cause of death were collected. A number of factors limit interpretation of results. Guidelines for the management of renal anemia and reimbursement varied for individual centers and countries. The design of ALTERNATE incorporated both retrospective and prospective collection of observational data after initiation of DA Q2W, which allowed for a large sample size and an increased rate of patient enrollment. However, observational studies, particularly those with retrospective design, may be limited by the lack of detailed data and missing data points. Hb concentrations remained remarkably steady throughout the study, and secondary analyses to ascertain the effects of missing data and changes in ESA treatment after the initiation of DA Q2W yielded comparable results (data not shown) to the data reported here. It is unlikely that these factors had a marked effect on the overall results. This initial report of the ALTERNATE study details the study design and methods of this large, longitudinal, observational study in dialysis patients receiving DAQ2W for anemia. These data provide support for translation of treatment recommendations developed from controlled trials to the clinical practice setting. Acknowledgment This study was sponsored by Amgen (Europe) GmbH, Zug, Switzerland. Johan De Meester has received consultancy fees and speaker fees from Amgen. Lawrence McMahon has received consultancy fees from Amgen. The authors wish to thank the participating dialysis centers and investigators for contributions to the study and data collection (see online supplemental information). We also wish to thank Janet Addison (Amgen Ltd. Uxbridge, UK) for the clinical study management and operations; Dikran Toroser (Amgen), Lucy Hyatt (Amgen (Europe) GmbH) and Michael Raffin (services retained by Amgen) for medical writing assistance; Tony Mossman (Amgen, Cambridge, UK) for statistical support; and Susan Wieting (Amgen (Europe) GmbH, Zug, Switzerland) for editorial support.

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