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Farxiga improved symptom burden and health-related quality of life in patients with mildly reduced or preserved ejection fraction in DELIVER Phase III trial

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Results presented at American Heart Association (AHA) Scientific Sessions 2022 and being published in the Journal of the American College of Cardiology. 
Clinical benefits were observed within two weeks with Farxiga, highlighting the importance of early treatment initiation.

New findings from a pre-specified analysis of DELIVER Phase III trial data show that AstraZeneca’s Farxiga (dapagliflozin) improved symptom burden and health-related quality of life in patients with heart failure (HF) and mildly reduced or preserved ejection fraction (EF) compared with placebo1. The results were presented today at the American Heart Association (AHA) Scientific Sessions 2022 in Chicago, Illinois, US, and are currently in press in the Journal of the American College of Cardiology.

In addition to the greater risk of death and hospitalisations, patients with HF and mildly reduced or preserved EF experience an especially high burden of symptoms and physical limitations, and a poor quality of life, which is why improving health status is a key goal of management1. In a prespecified analysis of the DELIVER Phase III trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was utilised to examine the effects of Farxiga on a broad range of health outcomes1.

In the analysis, Farxiga, in addition to standard care compared with placebo, improved symptom burden, physical limitations and quality of life as measured by mean KCCQ scores, with benefits achieved as early as one month1. Benefits were sustained at eight months, with mean improvement in total symptom score of 2.4 points, physical limitations 1.9 points, clinical summary 2.3 points and overall summary 2.1 points higher than placebo (all p <0.001)1. Also at eight months, fewer patients treated with Farxiga compared to placebo had a significant deterioration, and more had at least small, moderate and large (at least 5-, at least 10- and at least 15-point, respectively) improvements in health status across evaluated KCCQ domains1. The benefits of Farxiga on cardiovascular (CV) death and worsening HF in patients with mildly reduced or preserved EF appeared especially pronounced in those with greater degree of symptomatic impairment at baseline1.

Dr. Mikhail Kosiborod, cardiologist at Saint Luke’s Mid America Heart Institute, Vice President of Research at Saint Luke’s Health System, Professor of Medicine at the University of Missouri-Kansas City, said: “Many patients living with heart failure value their symptoms and physical function at least equally with avoidance of death, making these results highly clinically relevant. Given the fact that individuals with heart failure and mildly reduced and preserved ejection fraction experience especially poor health status, the findings should prompt clinicians to strongly consider initiation of SGLT2 inhibitors in this group, particularly if patients are symptomatic.”

The results support the 2022 joint HF guidelines issued by the American College of Cardiology, the American Heart Association and the Heart Failure Society of America, recommending broader use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in clinical practice and earlier initiation of guideline-directed medical therapy2.

Furthermore, these data align with the recent JAMA Cardiology publication, Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial, which demonstrated early and sustained reductions in clinical events in patients with HF and mildly reduced or preserved EF with statistically significant benefits observed within two weeks of treatment initiation3.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said:

“Recently Farxiga became the first heart failure medication ever to demonstrate mortality benefit across the full ejection fraction range, and now we also have data from the DELIVER trial showing that the health-related quality of life of patients with heart failure is significantly improved. Coupled with the rapid clinical benefits seen within two weeks, the data support the use of Farxiga as foundational therapy and highlight key opportunities for clinicians to implement the guidelines and upgrade patient outcomes.”

The safety and tolerability profile of Farxiga in the DELIVER Phase III trial was consistent with the well-established safety profile of the medicine4.

Notes

HF
HF is a chronic, long-term condition that worsens over time5. It affects nearly 64 million people globally with increasing prevalence and is associated with substantial morbidity and mortality6,7. Chronic HF is the leading cause of hospitalisation for those over the age of 65 and represents a significant clinical and economic burden8. There are several types of HF often defined by LVEF, a measurement of the percentage of blood leaving the heart each time it contracts, 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%)2. Approximately half of all HF patients have HFmrEF or HFpEF, with few therapeutic options available2,9.

DELIVER
DELIVER was an international, randomised, double-blind 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)10. Farxiga was given once daily in addition to background therapy (regional standard of care for all comorbidities, including diabetes and hypertension, with the exception of concomitant use of a SGLT2 inhibitor)10. DELIVER is the largest clinical trial to date in HF patients with LVEF above 40%, with 6,263 randomised patients10.

The primary endpoint was the time to first occurrence of CV death, hospitalisation for HF or an urgent HF visit10. The secondary endpoint includes the total number of HF events and CV death, time to the occurrence of CV death and time to the occurrence of death from any cause10. In addition, KCCQ total symptom score was a pre-specified key secondary endpoint as well as physical limitations, clinical summary and overall summary and were evaluated at randomisation, 1, 4 and 8 months1.

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 pancreas11-13. Damage to one of these organs can cause the other organs to fail, contributing to leading causes of death worldwide, including T2D, HF and chronic kidney disease (CKD)6,14-16.

Farxiga is approved for 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 and the treatment of CKD based on the findings of the DAPA-HF and DAPA-CKD Phase III trials.

DapaCare is a robust programme of clinical trials to evaluate the potential CV, renal and organ protection benefits of Farxiga. It includes more than 35 completed and ongoing Phase IIb/III trials in more than 35,000 patients, as well as more than 2.5 million patient-years’ experience. Farxiga is currently being tested in patients without T2D following an acute myocardial infarction or heart attack in the DAPA-MI Phase III trial - a first of its kind, indication-seeking, registry-based, randomised controlled trial.

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.

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References

  1. Kosiborod MN, et al. The effects of dapagliflozin on symptoms, function and quality of life in patients with heart failure and mildly reduced or preserved ejection fraction: results from the DELIVER Trial. Presented at: American Heart Association (AHA) Scientific Sessions 2022, 5-7 November 2022, Chicago, Illinois, USA.
  2. 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. Circulation. 2022;145:e895–e1032.
  3. Vaduganathan M, et al. Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. 2022; 2380-6583.
  4. Solomon S, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med 2022.
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  8. Azad N, et al. Management of chronic heart failure in the older population. J Geriatr Cardiol. 2014;11(4):329–37.
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  10. 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):1217–25.
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  12. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.
  13. 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):347–57.
  14. Mayo Clinic [Internet]. Heart failure, 2020; [cited 2022 Oct 06]. Available from: https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142.
  15. Centers for Disease Control and Prevention (CDC) [Internet]. A snapshot: Diabetes in the United States, 2020; [cited 2022 Oct 06]. Available from: https://www.cdc.gov/diabetes/library/socialmedia/infographics/diabetes.html.
  16. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Internet]. Heart disease & kidney disease, 2016; [cited 2022 Oct 06]. Available from: https://www.niddk.nih.gov/health-information/kidney-disease/heart-disease.

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