Farxiga demonstrated consistent benefit regardless of heart failure duration and across the full spectrum of cardiorenal disease

Two new analyses from the DELIVER Phase III trial presented at European Society of Cardiology’s Heart Failure 2023 congress in Prague, Czech Republic support the consistent benefits of Farxiga regardless of heart failure (HF) duration¹ and across the spectrum of cardiovascular, renal and metabolic (CVRM) conditions.²

Prespecified analysis of the DELIVER Phase III trial examined the treatment effect of Farxiga in patients with left ventricular ejection fraction (LVEF) greater than 40% based on how long they have had HF: ≤6 months, >6-12 months, >1-2 years, >2-5 years and >5 years. Results showed the benefit of Farxiga was consistent across all categories, regardless of HF duration.¹ Furthermore, the absolute benefit was increased in longer-standing HF patients who were older, had one or more comorbidity and had higher rates of worsening HF and death (number needed to treat, NNT: 24 vs 32 for patients with HF duration >5 years and ≤6 months duration respectively).¹

Additional post hoc analysis from the DELIVER Phase III trial was also presented and simultaneously published in JACC Heart Failure,² evaluating the prevalence of overlapping CVRM conditions and participants’ response to Farxiga at each intersection. The results showed that more than 4 in 5 patients with HF and LVEF greater than 40% had at least one other concomitant CVRM condition, and 1 in 5 had three CVRM conditions in addition to HF. Farxiga was well-tolerated and its treatment benefits were consistent irrespective of CVRM condition.²

Dr. Scott Solomon, Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital and Principal Investigator of the DELIVER Phase III trial, said: “In current clinical practice, patients with long-standing heart failure may be seen as having advanced disease that will not respond to or tolerate the addition of new therapies. Still, data from the DELIVER Phase III trial show it is never too late for patients to benefit from treatment with an SGLT2 inhibitor such as dapagliflozin, which maintained consistent benefits across different heart failure durations. This data contributes to the growing body of evidence on the efficacy of dapagliflozin in heart failure, demonstrating that it can help long-standing patients as much as someone who is newly diagnosed.”

Ruud Dobber, Executive Vice-President, BioPharmaceuticals Business Unit, AstraZeneca, said: “The impact of CVRM diseases on both patients and wider society are immense, yet these patients remain underdiagnosed, undertreated and their interconnections under-recognised. Findings from the DELIVER Phase III trial highlight how common it is for heart failure patients to have other CVRM conditions, such as type-2 diabetes and chronic kidney disease. These analyses further demonstrate the value of Farxiga as it brings benefit across all cardiorenal conditions and underscores our commitment to fundamentally transform care for millions of patients with heart failure and other CVRM conditions.”

HF is a chronic, long-term condition that worsens over time³ and approximately half of HF patients die within five years of diagnosis.⁴ It is often complicated by interconnected CVRM conditions, making it even more difficult to manage.⁵ Up to one in five people with chronic kidney disease (CKD) will develop HF, the leading cardiovascular (CV) complication among this group of patients.^6,7

These findings build upon the previously reported results from the DELIVER and DAPA-HF Phase III trials, which provide evidence to support the use of Farxiga as foundational therapy for patients with HF, and confirms Farxiga as the only heart failure medication to demonstrate mortality benefit regardless of ejection fraction (EF).^8,9

The safety and tolerability profile of Farxiga in the DELIVER Phase III trial was consistent with the well-established safety profile of the medicine.

Notes

HF
HF is a chronic, long-term condition that worsens over time.³ It affects nearly 64 million people globally¹⁰ and is associated with substantial morbidity and mortality.⁴ Chronic HF is the leading cause of hospitalisation for those over the age of 65 and represents a significant clinical and economic burden.¹¹ There are several types of HF often defined by LVEF, a measurement of the percentage of blood leaving the heart each time it contracts¹², including: HF with reduced EF (HFrEF) (LVEF less than or equal to 40%), HF with mildly reduced EF (HFmrEF) (LVEF 41-49%) and HF with preserved EF (HFpEF) (LVEF greater than or equal to 50%).¹³ Approximately half of all HF patients have HFmrEF or HFpEF,¹⁴ with few therapeutic options available.

DELIVER
DELIVER was an international, randomised, double-blind, parallel-group, placebo-controlled, event-driven Phase III trial designed to evaluate the efficacy of Farxiga, compared with placebo, in the treatment of HF patients with LVEF greater than 40%, with or without type-2 diabetes (T2D). Farxiga was given once daily in addition to background therapy (regional SoC for all comorbidities, including diabetes and hypertension, with the exception of concomitant use of SGLT2 inhibitor).¹⁵ 

DELIVER is the largest clinical trial to date in HF patients with LVEF above 40%, with 6,263 randomised patients.¹⁵ Of the 6,263 DELIVER Phase III trial participants, HF alone was uncommon (13%), 1,952 (31%) had HF plus one additional CVRM condition, 2,245 (36%) had HF plus two additional CVRM conditions, and 1,236 (20%) had HF plus three additional CVRM conditions.²

The primary composite endpoint was the time to first occurrence of CV death, hospitalisations for HF (hHF) or an urgent HF visit. Key secondary endpoints include the total number of HF events (hHF or urgent HF visit) and CV death, change from baseline in the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at eight months, time to the occurrence of CV death and time to the occurrence of death from any cause.¹⁵

DAPA-HF
DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) was an international, multi-centre, parallel-group, randomised, double-blinded Phase III trial in 4,744 patients with HFrEF, with and without T2D), designed to evaluate the effect of Farxiga 10mg, compared with placebo, given once daily in addition to standard of care (SoC). The primary composite endpoint was time to the first occurrence of a worsening HF event (hospitalisation or equivalent event, i.e. an urgent HF visit), or CV death. The median duration of follow-up was 18.2 months. Key secondary endpoints included the total number of hHF (including repeat admissions) and CV deaths, change from baseline to 8 months in the total symptom score on the KCCQ.¹⁶

Farxiga
Farxiga (dapagliflozin) is a first-in-class, oral, once-daily SGLT2 inhibitor. Research has shown Farxiga’s efficacy in preventing and delaying cardiorenal disease, while also protecting the organs – important findings given the underlying links between the heart, kidneys and pancreas.^16-18 Damage to one of these organs can cause the other organs to fail, contributing to leading causes of death worldwide, including T2D, HF and CKD. ^{10, 19-21}

Farxiga is approved in adults and children aged 10 years and above for the treatment of insufficiently controlled T2D mellitus as an adjunct to diet and exercise. Farxiga is also approved for the treatment of HFrEF in adults and the treatment of CKD in adults based on the findings of the DAPA-HF and DAPA-CKD Phase III trials.

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 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 (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 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 astrazeneca.com and follow the Company on Twitter @AstraZeneca.

References

1. Kondo T, et al. Patient characteristics, outcomes, and effects of dapagliflozin according to the duration of heart failure: A prespecified analysis of the DELIVER trial. Presented at: Heart Failure 2023, 20-23 May 2023, Prague, Czech Republic.

2. Ostrominki J, et al. Cardio-renal-metabolic overlap, outcomes, and treatment with dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. JACC Heart Failure. 2023.

3. Cleveland Clinic [Internet]. Heart failure [cited 2023 May 15]. Available from: https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure.

4. Mozaffarian D, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):e38-360.

5. Savarese G, et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur J Heart Fail. 2021; doi: 10.1002/ejhf.2271. Epub ahead of print. PMID: 34132001

6. House AA et al. Heart failure in chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019; 95(6):1304–17.

7. Segall L et al. Heart failure in patients with chronic kidney disease: A systematic integrative review. Biomed Res Int 2014; 2014:937398

8. Solomon S, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387(12):1089-1098.

9. Jhund P, et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med. 2022; 28(9):1956-1964.

10. 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. Lancet. 2017;390(10100):1211-1259.

11. Azad N, et al. Management of chronic heart failure in the older population. J Geriatr Cardiol. 2014;11(4):329-337.

12. May Clinic [Internet]. Ejection fraction: What does it measure?. [cited 2023 May 16]. Available from: https://www.mayoclinic.org/tests-procedures/ekg/expert-answers/ejection-fraction/faq-20058286.

13. Heidenreich PA, 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. 2008;10(10):933-989.

14. McDonagh T, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599-3726.

15. Solomon SD, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021;23(7):1217-1225.

16. McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.

17. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.

18. Wiviott SD, et al; for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes [article and supplementary appendix]. N Engl J Med. 2019;380(4):347-357.

19. Mayo Clinic [Internet]. Heart failure [cited 2023 May 15]. Available from: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.

20. Centers for Disease Control and Prevention (CDC) [Internet]. A snapshot: Diabetes in the United States [cited 2023 May 15]. Available from: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes.html.

21. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Internet]. Heart disease & kidney disease [cited 2023 May 15]. Available from: https://www.niddk.nih.gov/health-information/kidney-disease/heart-disease