Iain C. Macdougall,Amy M. Meadowcroft,Allison Blackorby,Borut Cizman,Alexander R. Cobitz,Sergio Godoy,Vivekanand Jha,Kirsten L. Johansen,Gearoid McMahon,Gregorio T. Obrador,Muh Geot Wong,Ajay K. Singh
Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)
Anemia,Clinical trial,Dialysis,Erythropoiesis-stimulating agent,Hemoglobin
Introduction Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214). Conclusion This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.
Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment.

ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored.

Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214).

This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

Anemia is a common complication among patients with chronic kidney disease who are on dialysis (CKD-5D) [1, 2]. It is managed by a combination of erythropoiesis-stimulating agent (ESA) therapy and iron supplementation. Most patients respond well to treatment with an increment in hemoglobin (Hb) concentration, aiming for a goal of 10–11 g/dL in the USA and 10–12 g/dL in other parts of the world. However, a significant proportion of patients require high doses of ESA and some remain anemic, despite treatment even at high doses; supplemental blood transfusions are frequently required for these patients [3]. Currently, there is no consensus definition for ESA hyporesponsiveness [4, 5, 6, 7, 8, 9]; optional definitions have recently been explored [10]. The proportion of patients hyporesponsive to ESAs varies depending on the definition used but is generally in the region of 10–15% in maintenance CKD-5D patients [3, 7, 11]. Several studies have explored the causes and/or predictors of ESA hyporesponsiveness in CKD-5D patients [9, 10, 12, 13, 14, 15, 16]. Major causes include iron deficiency (either absolute or functional) [14], inflammation (acute or chronic) [12, 16], intercurrent infections [17], under-dialysis [18], and nutritional deficiencies [19]. Predictors of ESA hyporesponsiveness include the expected parameters of low Hb and high ESA doses, as well as low transferrin saturation (TSAT) and/or low ferritin [14], elevated markers of inflammation (high sensitivity C-reactive protein [hsCRP], ferritin) [12, 16], high hepcidin [12, 20], and low albumin [21]. The influence of demographic, socioeconomic, and geographic factors in determining hyporesponsiveness, as well as its pattern globally, is poorly understood. For some patients, no obvious cause or predictor for the hyporesponsiveness can be identified [22]. Given that ESA hyporesponsiveness has been linked to higher mortality and poor clinical outcomes [3, 11, 21], managing this subset of patients is important. There is some evidence that HIF-prolyl hydroxylase inhibitors (HIF-PHIs), a new class of investigational drugs for treating anemia in chronic kidney disease (CKD), may be as effective or more effective in correcting anemia in patients hyporesponsive to conventional ESA therapy [23, 24]. This is because they affect erythropoiesis not only by upregulating erythropoietin but also by upregulating certain other genes such as those involved in improving iron delivery to the erythron [25]. They also downregulate hepcidin indirectly, which enhances iron availability [26]. For these reasons, it is important to explore characteristics and predictors of ESA hyporesponsiveness in a CKD population that is treated with HIF-PHIs. We have therefore investigated ESA hyporesponsiveness in a global randomized CV outcomes study in chronic dialysis patients (Anemia Studies in chronic kidney disease: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis [ASCEND-D] trial [ASCEND-D; NCT02879305]), comparing an investigational HIF-PHI, daprodustat, with conventional ESA treatment [27].

The study was approved by the Ethics Committee at every participating institution and was conducted according to the recommendations of Good Clinical Practice and the Declaration of Helsinki. Detailed information about the study procedures and design, as well as the entry criteria, for the ASCEND-D study (which recruited participants from September 2016 to June 2018 and completed in November 2020) is discussed elsewhere [27]. Briefly, a total of 2,964 chronic dialysis patients were recruited for the ASCEND-D randomized controlled trial. All had been on chronic dialysis for >90 days prior to screening and were receiving maintenance ESA treatment; 89% were undergoing hemodialysis (Table 1). In addition, they had to be iron replete at baseline (ferritin >100 ng/mL and TSAT >20%) and could not have had anemia due to other causes. Dose titrations of daprodustat and the comparator ESA were specified in the trial protocol with the aim of achieving a target Hb of 10–11 g/dL. The co-primary objectives of the trial were to compare Hb efficacy and CV safety among patients receiving daprodustat versus those receiving comparator ESA. Several principal secondary superiority endpoints and other secondary endpoints were also prespecified in the trial protocol. Efficacy analyses for the ESA hyporesponder subgroup will be performed as outlined for the full study. For this study, the primary definition of ESA hyporesponsiveness included a two-part definition: a baseline ESA Resistance Index (ERI) ≥2 U/kg/week/g/L or treatment at baseline with a very high standardized ESA dose ≥450 U/kg/week. Baseline ERI was calculated as the dry weight-adjusted standardized weekly mean ESA dose (U/week/kg) divided by baseline Hb (g/L). The ERI threshold was based on the HERO study [5], while the latter ESA dose threshold encompasses participants at higher body weight for which the ERI calculation is less accurate [7]. An alternate, broader definition of ESA hyporesponsiveness, ERI ≥1.5 U/kg/week/g/L, was also explored. The standardized ESA dose was determined using ESA conversion factors [27]. Results are based on the in-stream database as of April 20, 2020. Final data may have changed prior to database lock. We examined the baseline characteristics of the entire intention-to-treat population (all the patients who had undergone randomization), as well as the “ESA hyporesponsive” group and the “ESA responsive” group (using the primary definition and alternate definition). In addition, factors associated with ESA hyporesponsiveness were determined using a stepwise logistic regression model to identify factors associated with this condition. A p value of <0.10 was required for a parameter to enter the model, and a p value of <0.20 was required for a parameter to remain in the model. The odds ratios (ORs) and p values were then calculated from the final model to describe the direction and strength of the relationship between the variable and hyporesponsive status, given the other variables in the final model are held constant. The primary definition of ESA hyporesponsiveness was used as the dependent variable. Baseline parameters included in the model are summarized in online supplementary Table S1 (for all online suppl. material, see www.karger.com/doi/10.1159/000528696), with body mass index (BMI), intravenous (IV) iron dose, laboratory values all treated as continuous variables. Since the primary hyporesponder definition included baseline ESA dose, Hb, and dry weight, these parameters were not included in the model. Additional model selection analyses were performed to observe the impact on the identified factors associated with ESA hyporesponsiveness if BMI was excluded given weight is part of the ERI calculations or if baseline hepcidin was included in the list of factors considered for the model, or if categorical factors were used instead of continuous factors for age, BMI, IV iron dose, and TSAT. Additionally, the model selection analysis was run using the alternate definition of ESA hyporesponsiveness. See online supplementary Table S2 for additional details and rationale for these analyses. After observing results from the model selection analyses, baseline characteristics for the ESA hyporesponsive and ESA responsive groups were summarized by region and for select countries. The “intention-to-treat” population was used for all summaries and analysis, and descriptive statistics in the form of number and percentage of patients or median and 25th (P25) and 75th (P75) percentiles are provided for baseline variables unless otherwise stated.

Of the 2,964 randomized patients, 354 (12%) were ESA hyporesponsive using the primary definition. By definition, patients in the ESA hyporesponsive group had a lower Hb, a higher ESA dose, and a higher ERI than those in the ESA responsive group and in the overall study population, as shown at baseline (Table 1). In addition, ESA hyporesponsive patients had a higher hsCRP than responsive patients (median 6.0 mg/L vs. 3.8 mg/L, respectively) and lower TSAT (median 29% vs. 33%, respectively), suggesting a higher prevalence of inflammation. No difference in serum ferritin was observed among any of the groups, reflecting the protocol-specified requirement for iron repletion at baseline; likewise, hepcidin levels were similar across the groups. Region, lower baseline BMI and baseline TSAT, younger age, lower baseline albumin concentration, and a higher baseline IV iron dose were identified by the model selection exercise as most strongly associated (i.e., p value < 0.001) with ESA hyporesponsiveness (Table 2). Female sex and a history of heart failure were also associated with ESA hyporesponsiveness (p < 0.05). A longer time since dialysis initiation was moderately associated with ESA hyporesponsiveness (p < 0.10), while former or nonsmoker status, aspirin use, and ACEi/ARB use were less associated with ESA hyporesponsiveness (p > 0.10). Additional sensitivity model selection analyses also identified region to be most strongly associated with ESA hyporesponsiveness. The model excluding BMI largely mirrors the original model (online suppl. Table S3); the model considering baseline hepcidin found hsCRP to be a predictor of hyporesponsiveness but not hepcidin (online suppl. Table S4); and the model using categorical parameters eliminated baseline TSAT as a predictor, but elevated IV iron dose was a predictor of hyporesponsiveness (online suppl Table S5). Given that region consistently appeared as the factor most strongly associated with ESA hyporesponsiveness, regional variation was further explored by comparing ESA hyporesponsiveness in the four regions (North America [NAm]; Latin America [LA]; Europe, Middle East, and Africa [EMEA]; and Asia Pacific [APAC]) (Table 3). Compared with NAm, patients residing in EMEA were less likely to be ESA hyporesponders (OR [95% confidence interval (CI)] 0.32 [0.23–0.44]), whereas patients in LA were more likely to be ESA hyporesponders (OR 1.81 [CI: 1.3–2.51]); rates of hyporesponsiveness were similar between APAC and NAm (OR 0.99 [CI: 0.68–1.42]) (Table 2). When comparing the relative proportion of patients who were ESA hyporesponders by region, LA had the highest proportion, 4-fold higher than EMEA and 2-fold higher than NAm, while EMEA had the lowest proportion (Table 3). Online supplementary Table S6 includes comparison of baseline characteristics by region to allow for investigation of differences between the regions and ESA hyporesponsive status. As with the overall population, patients from all regions in the ESA hyporesponsive group had a lower Hb, a higher ESA dose, a higher ERI, and a higher hsCRP than those in the ESA responsive group. These values were generally similar across the regions except for a lower baseline Hb for ESA hyporesponders versus responders in LA (0.9 g/dL difference) and higher hsCRP values (for ESA hyporesponders/responders) in LA and NAm. While the proportion of peritoneal dialysis patients was 2-fold higher among those who were ESA hyporesponsive than ESA responsive in LA and NAm, dialysis adequacy was similar regardless of hyporesponder status. Minor differences were noted for hemodialysis frequency by region and ESA hyporesponsive status, but again, there was no difference in dialysis adequacy. CV history was lowest and baseline epoetin use was highest in LA versus the other regions, but they were similar for ESA hyporesponders and responders. Hospitalization within the last 6 months was highest in the ESA hyporesponsive group for APAC and LA. ESA hyporesponsiveness by country is summarized in Table 4. The countries with the highest level of ESA hyporesponsiveness (defined as >20% hyporesponders and at least 25 subjects) and lowest level (<5% and at least 25 subjects) are indicated shaded within the table; additional baseline details for these countries with the highest level of ESA hyporesponsiveness are provided in online supplementary Table 6. Country-level characteristics largely aligned with regional findings, with a few exceptions. Several characteristics of hyporesponders in India appeared different from those in the APAC region as a whole, including more patients dialyzing twice weekly, lower levels of dialysis adequacy, a lower Hb, more evidence of inflammation (higher hsCRP and ferritin), and greater use of IV iron. Within the LA region, several characteristics for Mexico stood out as different. For those who were ESA hyporesponsive, Mexico had more patients receiving twice-weekly hemodialysis, a higher proportion of women, more patients with a history of diabetes, and slightly more with dialysis access via a peritoneal dialysis catheter relative to the other LA countries but lower rates of IV iron use. After region, a lower baseline BMI was the next strongest parameter associated with ESA hyporesponsiveness (all <0.0001, where BMI was included). Figure 1a illustrates the proportion of patients who were ESA hyporesponsive or responsive at baseline, with those who were underweight being the most likely to be hyporesponsive. In addition, younger age, particularly those less than 40 years old (Fig. 1b), and a higher baseline IV iron dose, especially greater than 300 mg per month (Fig. 1c), were associated with ESA hyporesponsiveness. Lastly, using the alternate definition of hyporesponsiveness, 564 (20%) patients were ESA hyporesponsive. The baseline characteristics of those who were ESA hyporesponsive and ESA responsive are consistent with those identified by the primary definition. Likewise, the same factors most strongly associated with ESA hyporesponsiveness were identified by the model selection exercise, with region again appearing as the factor most strongly associated with ESA hyporesponsiveness. Results from the stepwise logistic regression model selection analysis, along with the corresponding ORs, are summarized in online supplementary Table S7.

ESA hyporesponsiveness is an important clinical issue because of its association with worse outcomes [3, 11, 21], increased cost of healthcare [10], and failure to achieve the desired Hb level. Here we report the characteristics and predictors of ESA hyporesponsiveness at baseline in the Phase 3 ASCEND-D trial. Our results show an overall prevalence of 12%, which is similar to that reported elsewhere using standard definitions. However, we found considerable variability in ESA hyporesponsiveness, both between and within regions. In particular, we observed a strikingly high rate of ESA hyporesponsiveness in LA and a very low rate (and in some cases, virtually no ESA hyporesponsiveness) within the EMEA countries. Within both the APAC and EMEA regions, certain countries such as Mexico and India had a relatively high rate of ESA hyporesponsiveness. Regional geography was the strongest independent predictor of hyporesponsiveness and supports the comments made by De Nicola et al. [28] in a review on responsiveness to ESAs in CKD. Furthermore, a DOPPS analysis which sought to evaluate regional differences in MACE rates, stratified by ESA hyporesponder status, also revealed some regional variation in ESA hyporesponsiveness but did not explore predictors as we have done in our current report [29]. Patients in this study showing ESA hyporesponsiveness tended to be younger, female, and with a lower BMI. Kalantar-Zadeh and colleagues, studying a large dialysis database, reported similar baseline characteristics, as well as higher parathyroid hormone levels and lower iron stores [14]. Female sex has indeed been associated with a poor response to ESA therapy in other studies [30], and the possible explanations for this include menstrual blood loss with a concomitant higher prevalence of iron deficiency, as well as lower testosterone levels; androgens are known to potentiate erythropoiesis which is believed to be the major cause of higher Hb levels in males in the general population [31]. Interestingly, other studies have found that older age and a higher BMI are both associated with ESA hyporesponsiveness [15], in contrast to the findings in the present study. Higher hsCRP levels and lower albumin levels, reflecting a greater degree of inflammation, have been reported in previous studies of ESA hyporesponsiveness [12, 13, 16, 20] and were also found in our study, although hsCRP was only identified as an independent predictor of hyporesponsiveness in the model where baseline hepcidin was included. A plausible explanation as to why hepcidin did not emerge in our model as a predictor is that hepcidin is also acting more downstream than hsCRP. hsCRP, as a marker of inflammation, might be expected to correlate more with hyporesponsiveness than hepcidin since the latter is affected by factors other than inflammation. In a study examining predictors of ESA hyporesponsiveness in a peritoneal dialysis population, Kim et al. [32] found a significant correlation with TSAT, dialysis adequacy, serum albumin level, normalized protein catabolic rate, and serum CRP, with the latter being the strongest predictor in a stepwise linear regression analysis. Almost identical predictors were subsequently found in another peritoneal dialysis study [33], as well as in a hemodialysis cohort of 1,934 patients followed for up to 2 years [34]. In the latter study, multivariate analysis revealed albumin, Kt/V, TSAT, statin use, and male gender to be inversely related to ERI, whereas parathyroid hormone and the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with ESA hyporesponsiveness [34]. We constructed a stepwise multivariable regression model to examine independent predictors of ESA hyporesponsiveness. Interestingly, in the first model, a lower TSAT was associated with hyporesponsiveness despite the study protocol mandating that patients were iron replete on entry to the study. Even though the TSATs for the ESA hyporesponsive (29%) and ESA responsive (33%) groups were consistent with clinical practice guidelines on CKD anemia management, the results suggest that ESA hyporesponsive patients may still possess a residual suboptimal iron delivery to the bone marrow. Indeed, the results of the PIVOTAL study [35] have suggested that conventionally accepted levels of TSAT may still be too low to optimize erythropoiesis and clinical outcomes. Other baseline variables in the model achieving statistical significance included age, BMI, albumin, IV iron dose, history of heart failure, dialysis vintage, smoking status, and aspirin use. In all models of the stepwise multivariable regression analysis using the primary definition, regional variation came out as a strong predictor of ESA hyporesponsiveness, and the fact that this was also true for the secondary definition adds to the robustness of this finding. The explanation for these findings is not immediately clear, although several potential factors may have played a part. First, the only finding that appears different across the various regions was the type of prior ESA used. For example, in LA, all patients were on short-acting epoetin, in contrast to the other regions where variable proportions of medium- and long-acting ESAs were used. Although data on the type of ESA were collected at baseline, we do not have data on the type of epoetin used. It is possible that greater quantities of less expensive but less effective unapproved biosimilar epoetin preparations were used in some of the countries in LA. In a survey conducted by the Latin American Society of Nephrology and Hypertension (SLANH) Anemia Committee, data were collected from 134 hemodialysis units in 16 countries, enrolling 9,025 hemodialysis patients [36]. Despite widespread use of ESA therapy and IV iron, nearly half of the patients did not achieve the recommended Hb target. The independent variables associated with a low Hb level (<10.5 g/dL) were female sex, TSAT <25%, and age <50 years [36]. Other reasons why region is a strong predictor of ESA hyporesponsiveness may include regional variations in the medical management of chronic dialysis patients. Third, there may be differences in access to healthcare, including inconsistent availability of ESA and iron therapy for chronic dialysis patients and greater use of biosimilar ESAs. These factors may also account for the higher prevalence of ESA hyporesponsiveness in India compared with the other APAC countries. However, there were also some notable differences in the prevalence of predictors of ESA hyporesponsiveness in India compared with the rest of the APAC region (higher prevalence of diabetes and under-dialysis, evidence of more inflammation manifested by higher CRP levels, and greater use of IV iron). Many reports on ESA hyporesponsiveness have used the ERI (calculated as weight-adjusted weekly ESA dose in IU/kg/week divided by the Hb concentration in g/dL [or g/L]), stratifying ESA hyporesponsiveness into ERI tertiles [4, 8, 9]. Similarly, the HERO study, a randomized controlled trial investigating the effects of pentoxifylline in patients with ESA hyporesponsiveness, defined hyporesponsiveness using ERI ≥2.0 IU/kg/week/g/L [5]. Accordingly, we adopted ERI ≥2.0 IU/kg/week/g/L as our primary definition of ESA hyporesponsiveness since it is reproducible across all groups and studies, in contrast to other definitions which rely more on the upper extreme of the ESA dose, thus introducing unnecessary bias caused by differences in practice patterns. To examine the robustness of our primary definition of ESA hyporesponsiveness, we performed a sensitivity analysis using an alternate definition based on the NICE guidelines [7]. NICE defines ESA hyporesponsiveness as being present when an aspirational Hb range is not achieved despite treatment with 300 IU/kg/week or more of subcutaneous epoetin, 450 IU/kg/week or more of IV epoetin, or 1.5 μg/kg/week of darbepoetin, or if there is a continued need for the administration of high doses of ESAs to maintain the aspirational Hb range [7]. There are a number of strengths of this study, including the large sample size of nearly 3,000 patients and the variety of regions and practices, inclusion of iron replete patients receiving at least minimal ESA doses at the start of the study, careful collection of data, the use of prespecified definitions and predictors of ESA hyporesponsiveness, and the incorporation of hepcidin in the analysis, the latter being an uncommon feature of studies in this field. Participants enrolled in ASCEND-D largely reflect real-world chronic dialysis patients [27]; however, because this is a randomized clinical trial, there were specific eligibility criteria that made it more restrictive. For example, the need for patients to be iron replete at baseline significantly reduced the chances of detecting iron deficiency as a factor causing ESA hyporesponsiveness, in contrast to many other previously published studies [14, 30]. Other limitations include the potential for false-positive findings due to the number of characteristics analyzed, the lack of citation of regional Hb targets, and the lack of citation of ESA reimbursement policies which could include the use of biosimilars. Additionally, there may have been other factors contributing to hyporesponsiveness in this study which would have been difficult or impossible to capture, such as genetic factors or financial incentives. Finally, it should be acknowledged that observational associations do not prove causation. In conclusion, this dataset from the ASCEND-D randomized clinical trial allowed us to investigate predictors of ESA hyporesponsiveness in a large global chronic dialysis cohort. Although many predictive factors have been reported previously or were expected, the regional variation in responsiveness to ESA therapy, particularly the striking difference between EMEA and LA, was a novel finding that merits further consideration.

The study was approved by the Ethics Committee at every participating institution and was conducted according to the recommendations of Good Clinical Practice and the Declaration of Helsinki. The study protocol was reviewed and approved by Quorem Review IRB, approval number 31745. The study protocol was reviewed and approved at each of the participating sites. The full list of participating sites can be found at Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Dialysis (ASCEND-D) – Full Text View – ClinicalTrials.gov. All patients provided written informed consent.

Iain C. Macdougall has received advisory fees from Vifor Pharma, provided advisory services to GSK, and is an ASCEND steering committee member. Sergio Godoy provides consultant services to George Clinical, which involve clinical trials for a range of sponsors. Vivekanand Jha has participated in scientific advisory boards for AstraZeneca, GSK and Boehringer Ingelheim and is an ASCEND steering committee member. Kirsten L. Johansen received ASN fees as JASN Associate Editor, has been an advisory board member for Akebia Therapeutics Inc. and GSK, and is an ASCEND steering committee member. Gearoid McMahon worked as a coordinator for GSK. Gregorio T. Obrador has been a conference speaker and an advisory board member for Roche Mexico, a National Leader for the CREDENCE trial for Janssen Research & Development, LLC, an advisory board member for GSK, and is an ASCEND steering committee member. Muh Geot Wong has received honorarium for scientific lectures from AstraZeneca, Retrophin, Amgen, and Baxter. His employer, the George Institute for Global Health, holds research contracts for trials in cardiovascular and/or kidney disease with a range of commercial organizations. Ajay K. Singh reports consultancy fees from GSK and is an ASCEND steering committee member, Zydus, and BayerAG. Allison Blackorby, Borut Cizman, Alexander R. Cobitz, and Amy M. Meadowcroft are employees of and stockholders in GSK.

The ASCEND-D study (ClinicalTrials.gov NCT02879305. EudraCT Number: 2016-000541-31) was funded by GSK (study 200807).

Iain C. Macdougall wrote the first draft in its entirety with no input from a medical writer. Iain C. Macdougall and Ajay K. Singh contributed to the design, interpretation of data, supervision, management of the research, writing, and critical review of this manuscript. Iain C. Macdougall, Amy M. Meadowcroft, Allison Blackorby, Borut Cizman, Alexander R. Cobitz, Sergio Godoy, Vivekanand Jha, Kirsten L. Johansen, Gearoid McMahon, Gregorio T. Obrador, Muh Geot Wong, and Ajay K. Singh contributed to the design, interpretation of data, management of research, writing, and critical review of this manuscript. Iain C. Macdougall, Amy M. Meadowcroft, Allison Blackorby, Borut Cizman, Alexander R. Cobitz, Sergio Godoy, Vivekanand Jha, Kirsten L. Johansen, Gearoid McMahon, Gregorio T. Obrador, Muh Geot Wong, and Ajay K. Singh affirm that authorship is merited based on the International Committee of Medical Journal Editors authorship criteria. Iain C. Macdougall and Ajay K. Singh were the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Within 6 months of this publication, anonymized individual participant data, the annotated case report form, protocol, reporting and analysis plan, dataset specifications, raw dataset, analysis-ready dataset, and clinical study report will be available for research proposals approved by an independent review committee. Proposals should be submitted to www.clinicalstudydatarequest.com. A data access agreement will be required. All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to corresponding author, Iain C. Macdougall.

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