ZORA real-world evidence demonstrates that LOKELMA substantially increases cardiorenal patients’ chances of maintaining lifesaving RAASi therapy

Treating hyperkalemia 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 hyperkalemia (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 hyperkalemia (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 CKD stage 5 or the initiation of dialysis, within 6 months following a hyperkalemia 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 hyperkalemia with a potassium binder allows guideline recommended RAASi therapy to be maintained at the optimized 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 hyperkalemia 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 hyperkalemia 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 real-world evidence (RWE) study indicates an urgent need for improved guideline adherence in managing HK to enable patients to stay on their lifesaving RAASi therapy.

IMPORTANT SAFETY INFORMATION FOR LOKELMA® (sodium zirconium cyclosilicate)

WARNINGS AND PRECAUTIONS:                                                                                                                              

  • Gastrointestinal Adverse Events in Patients with Motility Disorders: Avoid LOKELMA in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders. LOKELMA has not been studied in patients with these conditions and it may be ineffective and may worsen gastrointestinal conditions
  • Edema: Each 5-g dose of LOKELMA contains approximately 400 mg of sodium, but the extent of absorption by the patient is unknown. In clinical trials of LOKELMA in patients who were not on dialysis, edema was observed and was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily. Monitor for signs of edema, particularly in patients who should restrict their sodium intake or are prone to fluid overload (eg, heart failure or renal disease). Advise patients to adjust dietary sodium, if appropriate. Increase the dose of diuretics as needed
    • In a clinical trial of LOKELMA in patients on chronic hemodialysis in which most patients were treated with doses of 5 g to 10 g once daily on non-dialysis days, there was no difference in the mean change from baseline in interdialytic weight gain (a measure of fluid retention) between the LOKELMA and placebo groups
  • Hypokalemia in Patients on Hemodialysis: Patients on hemodialysis may be prone to acute illness that can increase the risk of hypokalemia on LOKELMA (eg, illnesses associated with decreased oral intake, diarrhea). Consider adjusting LOKELMA dose based on potassium levels in these settings
  • Diagnostic Tests: LOKELMA has radio-opaque properties and, therefore, may give the appearance typical of an imaging agent during abdominal X-ray procedures

ADVERSE REACTIONS: The most common adverse reaction in non-dialysis patients with LOKELMA was mild to moderate edema. In placebo-controlled trials up to 28 days, edema was reported in 4.4%, 5.9%, 16.1% of non-dialysis patients treated with 5 g, 10 g, and 15 g of LOKELMA once daily, respectively vs 2.4% of non-dialysis patients receiving placebo.

DRUG INTERACTIONS: LOKELMA can transiently increase gastric pH. In general, oral medications with pH-dependent solubility should be administered at least 2 hours before or 2 hours after LOKELMA. Spacing is not needed if it has been determined the concomitant medication does not exhibit pH-dependent solubility.

INDICATION AND LIMITATION OF USE

LOKELMA is indicated for the treatment of hyperkalemia in adults.

LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.

Please read full Prescribing Information for LOKELMA.

Notes

Hyperkalemia
Hyperkalemia (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 hyperkalemia.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 program, which is examining the current management of HK and its clinical consequences. The ZORA study ‘Maintained RAASi Therapy with Sodium Zirconium Cyclosilicate Following a Hyperkalemia 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 Hyperkalemic 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 categorized as down titrated, discontinued, or maintained RAASi treatment.2

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three 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 and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases, and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

AstraZeneca 
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, 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  www.astrazeneca-us.com and follow us on social media @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.