The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

Johansen, Kirsten L.; Cobitz, Alexander R.; Singh, Ajay K.; Macdougall, Iain C.; Lópes, Renato D.; Obrador, Gregorio T.; Kövesdy, Csaba P.; Israni, Rubeen; Jha, Vivekanand; Okoro, Tony; Sprys, Mike; Jolly, Shivinder; Bhatt, Praghnesh; Camejo, Rodrigo Refoios; Keeley, Tom; Čižman, Borut; Wheeler, David C.

doi:10.1016/j.kint.2023.02.019

Cited by 25 publications

(14 citation statements)

References 24 publications

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“…However, only the study with desidustat reported an analysis of the increase of the quality-of-life score during treatment, showing similar improvement of SF-36 from baseline with desidustat and darbepoetin alfa [45]. Efficacy of HIF-PHIs in improving HRQoL has also been reported in a study with daprodustat, published at present, only in abstract form; however, considering the paucity of available data and the large number of enrolled patients, we think it is worthwhile to report [130]. In this study, Johansen et al [130] randomised 614 ND-CKD anaemic patients to daprodustat or placebo for 28 weeks to compare their effects on HRQoL.…”

Section: Quality Of Lifementioning

confidence: 72%

“…Efficacy of HIF-PHIs in improving HRQoL has also been reported in a study with daprodustat, published at present, only in abstract form; however, considering the paucity of available data and the large number of enrolled patients, we think it is worthwhile to report [130]. In this study, Johansen et al [130] randomised 614 ND-CKD anaemic patients to daprodustat or placebo for 28 weeks to compare their effects on HRQoL. The authors found that SF-36 Vitality (fatigue) score significantly increased with daprodustat versus placebo (+ 7.3 vs + 1.9 points), with a higher proportion of vitality responders (≥ 6-point increase) in patients receiving daprodustat (58% vs 40%); the cognitive domain was also significantly improved by daprodustat [130].…”

Section: Quality Of Lifementioning

confidence: 79%

“…The authors found that SF-36 Vitality (fatigue) score significantly increased with daprodustat versus placebo (+ 7.3 vs + 1.9 points), with a higher proportion of vitality responders (≥ 6-point increase) in patients receiving daprodustat (58% vs 40%); the cognitive domain was also significantly improved by daprodustat [130]. Better HRQoL paralleled with better anaemia control (Hb increase from baseline + 1.58 vs + 0.19 with daprodustat and placebo, respectively; p < 0.001) [130], thus confirming that anaemia correction translates into improved quality of life. However, whether treatment with HIF-PHIs is superior in comparison to ESA remains undefined.…”

Section: Quality Of Lifementioning

confidence: 99%

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Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Locatelli

Minutolo²,

Nicola³

et al. 2022

Drugs

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Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

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Section: Quality Of Lifementioning

confidence: 72%

Section: Quality Of Lifementioning

confidence: 79%

Section: Quality Of Lifementioning

confidence: 99%

See 1 more Smart Citation

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Locatelli

Minutolo²,

Nicola³

et al. 2022

Drugs

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show abstract

“…Unfortunately, this aspect has not really been considered by RCTs in the field. The preliminary findings of the Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat in Non-dialysis Subjects Evaluating Hemoglobin and Quality of Life (ASCEND-NHQ) 120 showed a statistically significant improvement of the vitality score (fatigue) in comparison with placebo in ESA-naïve nondialysis patients. Not only were achieved Hb levels markedly differed in the two groups, but also the Hb target (11–12 g/dl) was higher than that of the other ASCEND trials and of that indicated in the request for FDA approval (10–11 g/dl).…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Hypoxia-Inducible Factor–Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

Locatelli

Vecchio

2022

JASN

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Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESA) and iron. Experimental studies extensively investigated the mechanisms involved in the body's response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESA. Overall, data from phase-II and III clinical development showed efficacy in anemia correction and maintenance for all the class molecules compared to placebo (superiority) or erythropoiesis-stimulating agents (non-inferiority). Three molecules, roxadustat, vadadustat and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular endpoints, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the non-dialysis population, at the prespecified primary analyses, all the three molecules met the non-inferiority margin for the risk of major cardiovascular events compared to erythropoiesis stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared to already available ESA.

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“…Like injectable ESAs, daprodustat has not been shown to improve quality of life (QoL) in patients on dialysis but was associated with improved fatigue in a study of patients with nondialysis-dependent CKD. 4 The question now is where daprodustat fits in for the treatment of anemia in patients on maintenance dialysis in the United States. In considering this, one might think of several distinct patient populations: patients on in-center hemodialysis or home dialysis (peritoneal and hemodialysis) who are doing well on an injectable ESA (maintaining the desired hemoglobin level with a reasonable ESA dose), and those in any setting who are hyporesponsive to injectable ESAs, on the basis of failure to achieve target hemoglobin or requiring very high doses to do so.…”

mentioning

confidence: 99%

What Is the Role of Daprodustat in Treatment of Anemia in People on Maintenance Dialysis?

Berns

2023

CJASN

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The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

Cited by 25 publications

References 24 publications

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Hypoxia-Inducible Factor–Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

What Is the Role of Daprodustat in Treatment of Anemia in People on Maintenance Dialysis?

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