ZORA real-world evidence demonstrates that Lokelma substantially increases cardiorenal patients’ chances of maintaining lifesaving RAASi therapy
Treating hyperkalaemia with Lokelma more than doubled the odds (by ~2.5 times) of patients maintaining guideline RAASi therapy versus no potassium binder treatment
Renal patients who stopped RAASi therapy had a 73% higher risk of progression to end-stage kidney disease within 6 months
Results from the real-world ZORA observational multi-country study presented today at the American Society of Nephrology (ASN) 2023 shows that treating hyperkalaemia (HK) with the potassium binder Lokelma (sodium zirconium cyclosilicate) can allow patients with chronic kidney disease (CKD) or heart failure (HF) to maintain their lifesaving renin-angiotensin-aldosterone system inhibitor (RAASi) therapy.1
Analysis showed that patients treated with Lokelma were substantially more likely to maintain guideline-recommended RAASi therapy at 6 months following a hyperkalaemia (HK) episode, compared to patients who were not treated with a potassium binder, the odds were ~2.5-times higher (OR 2.56; 95% CI: 1.92–3.41; P<0.0001).1
Additional analysis also showed that the risk of progression to end-stage kidney disease (ESKD), diagnosed as chronic kidney disease (CKD) stage 5 or the initiation of dialysis, within 6 months following a hyperkalaemia episode was 73% higher in patients who discontinued RAASi treatment, and 60% higher in patients who down-titrated vs maintained RAASi therapy.2 This builds on previous data showing that HK-related RAASi reduction increases the risk of cardiorenal events and mortality among patients with CKD or HF.3,4
Anjay Rastogi, M.D., Ph.D., Clinical Chief of Nephrology, UCLA Health, said: "Evolving science shows that proactive management of hyperkalaemia with a potassium binder allows guideline recommended RAASi therapy to be maintained at the optimised dose levels to improve outcomes for patients with CKD or heart failure. Yet, real-world evidence provides a sharp reality check of what’s actually happening to cardiorenal patients following an episode of hyperkalaemia in clinical practice and the serious consequences down-titration and discontinuation of RAASi therapy can have, leading to poorer outcomes and increased mortality."
Ruud Dobber, Executive Vice-President, BioPharmaceuticals Business Unit, AstraZeneca, said: “These data add to the body of evidence that if hyperkalaemia is not effectively managed, it can lead to worsening cardiovascular and kidney disease outcomes and increased mortality due to down-titration or discontinuation of RAASi. Lokelma can be a pivotal therapeutic strategy to address this urgent disease burden. At AstraZeneca, we remain committed to working with the cardiorenal community to enable guideline recommended RAASi therapy and achieve more effective cardiorenal protection for patients.”
This RWE study indicates an urgent need for improved guideline adherence in managing HK to enable patients to stay on their lifesaving RAASi therapy.
Notes
Hyperkalaemia
Hyperkalaemia (HK) can be a chronic condition characterised by high levels of potassium in the blood, generally defined as greater than 5 mmol/L.5,6 Patients with high potassium levels are at significant risk of cardiac arrhythmias, which can lead to cardiac arrest.7 Worldwide there are about 840 million and 64 million people living with CKD and HF respectively, who are at an estimated 2 to 3 times higher risk of hyperkalaemia.8-11 RAASi therapy is guideline-recommended to slow down CKD progression and reduce CV events, but it is often lowered or discontinued when HK is diagnosed.12-15 This has been shown to negatively impact patient outcomes, with mortality rates doubled for patients with CKD and HF whose RAASi had been down-titrated or discontinued compared to patients on maximum RAASi dose.16
ZORA
The ZORA study is a global RWE programme, which is examining the current management of HK and its’ clinical consequences. The ZORA study ‘Maintained RAASi Therapy with Sodium Zirconium Cyclosilicate Following a Hyperkalaemia Episode' used health registers and hospital medical records to identify patients with CKD and/or HF receiving RAASi therapy who experienced a HK episode.1 The SZC cohort included 565 (US), 776 (Japan), and 56 (Spain) patients treated with SZC for at least 120 days; the No K+ binder cohort included 2068 (US), 2629 (Japan), and 203 (Spain) patients without a K+ binder prescription.1 Propensity score (PS) matching was applied to balance the SZC cohort to the No K+ binder cohort on baseline characteristics.1 The second ZORA study on ‘Association Between Reduced RAASi Therapy and Progression to ESKD in Hyperkalaemic CKD Patients’ included 11,873 (US) and 1427 (Japan) patients with CKD Stage 3/4 and baseline RAASi use who experienced an HK episode.2 Based on RAASi prescriptions 3 months before versus after the HK episode, patients were categorised as down titrated, discontinued, or maintained RAASi treatment.2
Lokelma
Lokelma (sodium zirconium cyclosilicate) is an anti-hyperkalaemia (HK) therapy that provides rapid K+ reduction and sustained K+ control.17 It is indicated for the treatment of HK in adults, including patients with ESKD on chronic haemodialysis, to only be dosed on non-dialysis days.18 It is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly selective potassium-removing medicine.18 It is administered orally and is odourless, tasteless, and stable at room temperature.18-19 Lokelma has been approved in more than 50 countries including the US, EU and Japan.20
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s main disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys, liver and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection by slowing or stopping disease progression, and ultimately paving the way towards regenerative therapies. The Company's ambition is to improve and save the lives of millions of people, by better understanding the interconnections between CVRM diseases and targeting the mechanisms that drive them, so we can detect, diagnose, and treat people earlier and more effectively.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Disease, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
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References
1. Rastogi A, et al. ZORA: Maintained RAASi Therapy with Sodium Zirconium Cyclosilicate Following a Hyperkalaemia Episode: A Multi-Country Cohort Study, presented at American Society of Nephrology Kidney Week, 1-5th November 2023, Philadelphia, PA, USA
2. Rastogi A, et al. ZORA: Association between reduced RAASi therapy and progression to ESKD in hyperkalaemic CKD patients, presented at American Society of Nephrology Kidney Week, 1-5th November 2023, Philadelphia, PA, USA
3. Kanda E, et al. Clinical impact of suboptimal RAASi therapy following an episode of hyperkalemia. BMC Nephrol. 2023. doi: 10.1186/s12882-022-03054-5.
4. Epstein M, et al. Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena. Kidney Int Suppl (2011). 2016 Apr;6(1):20-28. doi: 10.1016/j.kisu.2016.01.004. Epub 2016 Mar 14.
5. Thomsen RW et al. Elevated Potassium levels in patients with chronic kidney disease; occurrence, risk factors and clinical outcomes – a Danish population-based cohort study. J Am Heart Assoc. 2018;7:e008912
6. Kovesdy CP, et al.Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol. Nov 2014;10:653-662
7. Kovesdy CP, et al. Serum and Dialysate Potassium Concentrations and Survival in Hemodialysis Patients. Clin J Am Soc Nephrol. 2007:2:999-1007.
8. Jain N, et al. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol. 2012;109(10):1510-1513.
9. Sarwar, et al. Hyperkalemia in Heart Failure. J Am Coll Cardiol. 2016;68(14):1575-1589.
10. Jager KJ, et al. A Single Number for Advocacy and Communication—Worldwide More than 850 Million Individuals Have Kidney Diseases. Nephrol Dial Transplant. 2019;34(11):1803-5.
11. Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet 2017; 390(10100):1211–59.
12. McDonagh TA ,et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.
13. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421.
14. Collins AJ, et al. Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes. Am J Nephrol. 2017;46(3):213-221.
15. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022;102(5S):S1-S127.
16. Epstein et al. Evaluation of the Treatment Gap Between Clinical Guidelines and the Utilization of Renin-Angiotensin Aldosterone System Inhibitors. Am J Manag Care. 2015;21(11 suppl):S212-S220.
17. Kosiborod M, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [article and protocol]. JAMA. 2014;312:2223-2233.
18. European Medicines Agency [Internet] Lokelma (sodium zirconium cyclosilicate). Summary of Product Characteristics; [cited 12 Oct 2023]. Available at: URL: https://www.ema.europa.eu/en/documents/product-information/lokelma-epar-product-information_en.pdf
19. Lokelma® (sodium zirconium cyclosilicate) for oral suspension [Internet]. US prescribing information. Wilmington (DE): AstraZeneca Pharmaceuticals LP; [cited 12 Oct 2023]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207078s003lbl.pdf
20. AstraZeneca. Data on file. [REF-198643]
