Cardiovascular safety of current and emerging drugs to treat anaemia in chronic kidney disease: a safety review

ABSTRACT

Introduction

Erythropoiesis-stimulating agents (ESAs) are the standard of treatment for anemia in chronic kidney disease. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) are small molecules that stimulate endogenous erythropoietin synthesis.

Areas covered

The cardiovascular safety of ESAs and HIF-PHIs. We performed a PubMed search using several key words, including anemia, chronic kidney disease, safety, erythropoiesis stimulating agents, HIF-PH inhibitors.

Expert opinion

ESAs are well-tolerated drugs with a long history of use; there are safety concerns, especially when targeting high hemoglobin levels. HIF-PHIs have comparable efficacy to ESAs in correcting anemia. Contrary to expectations, randomized phase 3 clinical trials have shown that overall HIF-PHIs were non-inferior to ESA or placebo with respect to the risk of cardiovascular endpoints. In addition, some phase 3 trials raised potential safety concerns regarding cardiovascular and thrombotic events, particularly in non-dialysis patients.

Today, HIF-PHIs represent an additional treatment option for anemia in patients with chronic kidney disease. This has made the management of anemia in CKD more complex and heterogeneous. A better understanding of the mechanisms causing hypo-responsiveness to ESAs, combined with an individualized approach that balances ESAs, HIF-PHIs and iron doses, could increase the benefits while reducing the risks.

KEYWORDS:

• Anemia
• erythropoiesis-stimulating agents
• chronic kidney disease
• cardiovascular risk
• hypoxia-inducible factor prolyl hydroxylase inhibitors
• hyporesponsiveness

Article highlights

• Treatment of CKD anemia includes iron, erythropoiesis-stimulating agents (ESAs) and, ultimately, blood transfusions.

• Despite their efficacy, the safety of high-dose iron and ESAs is a matter of lively debate.

• The use of ESAs at high doses and when aiming for near-normal hemoglobin levels has been associated with an increased risk of mortality, CV events, cancer and thrombosis.

• New molecules have been developed that inhibit prolyl hydroxylase (PH) enzymes, thereby increasing the activity of hypoxia-inducible factors (HIF).

• They effectively correct anemia in non-dialysis and dialysis patients.

• These oral drugs have not shown a better safety profile than ESAs.

• HIF-PH inhibitors should be considered as an alternative to current ESAs, especially in patients with inflammation.

Key messages

1. Anemia is a common complication of CKD and is associated with poor outcomes and quality of life.

2. The use of ESAs to normalize Hb levels is associated with an increased risk of CV and thrombotic events. Accordingly, the Hb target to be achieved with ESA has been progressively lowered.

3. European Renal Best Practice suggests an Hb target of 10-12 g/dL and individualized management.

4. KDIGO guidelines suggest a more conservative approach (<11.5 g/dL).

5. Hyporesponsiveness to ESAs and inflammation play an independent role in adverse patient outcomes.

6. Treatment with intravenous iron may reduce CV risk in patients with heart failure, independent of anemia.

7. Proactive iron administration reduces CV risk in hemodialysis patients on ESA treatment.

8. HIF-PHI have a different mechanism of action from ESAs and represent an alternative option for the treatment of anemia. Available CV safety data show at best non-inferiority to ESAs.

Declaration of interests

F Locatelli is or was a member of an advisory board of Amgen, Astellas, Baxter, GSK, Otsuka, Travere, and Vifor Pharma and speaker at meetings supported by an unrestricted grant from Amgen, Astellas and Vifor Pharma. E Paoletti acts as consultant for, and received fees from AstraZeneca; VIFOR Pharma; Astellas; Novartis; GSK; Bayer. L Del Vecchio participated to Advisory Boards for Astellas, GSK, Travere, and she received speaker fees at meeting support directly or indirectly by Astellas, Amgen, Vifor Pharma, AstraZeneca, Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer is a consultant to GSK, developer of daprodustat. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Author contribution statement

All three authors equally contributed to the conception, writing and revision of the manuscript.

Additional information

Funding

This paper was not funded.