Consistent effects of Farxiga in heart failure patients with reduced ejection fraction shown in new analyses from landmark Phase III DAPA-HF trial

Data were consistent in patients with and without type-2 diabetes, showed early effects in the first month and improvement in patient-reported outcomes
 

AstraZeneca today announced new data from five additional analyses of the landmark Phase III DAPA-HF trial, which showed that Farxiga (dapagliflozin) reduced the risk of the primary composite outcome of worsening heart failure (HF), defined as hospitalisation or an urgent visit, or death from cardiovascular (CV) causes versus placebo, when added to standard of care.

DAPA-HF is the first outcomes trial with an SGLT2 inhibitor investigating the treatment of HF in patients with reduced ejection fraction (HFrEF), with and without type-2 diabetes (T2D). The new analyses showed the consistency of these results across patient subgroups with and without T2D, an early onset of effects, and improvement in patient-reported outcomes of HF-related health status.  

These data were presented at the American Heart Association (AHA) Scientific Sessions in Philadelphia, Pennsylvania, US.

Elisabeth Björk, Senior Vice President, Head of Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, said: “Heart failure affects approximately 64 million people around the world and about half of those patients will die within five years of diagnosis.^1,2 These new analyses from the DAPA-HF trial reinforce the science behind Farxiga as clinically significant across heart failure patient populations and suggest the potential to improve the current standard of care for millions of these patients.”

Across all five analyses, Farxiga showed improvements versus placebo in the worsening or progression of the disease and improved patient-reported symptoms and quality of life.

The Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure Trial (DAPA-HF): Results in Nondiabetic Patients subgroup analysis showed that Farxiga reduced the risk of the primary composite endpoint compared to placebo in patients with HFrEF without T2D. This analysis evaluated the primary composite and its components and secondary endpoints in a subgroup of patients without T2D. With Farxiga, the relative risk of the composite of worsening of HF or CV death was reduced by 27% among participants without diabetes (absolute risks 9.2% vs. 12.7%, n=2605; HR 0.73; 95% CI 0.60, 0.88) and by 25% in patients with diabetes (14.6% vs. 19.4%, n=2139; HR 0.75; 95% CI 0.63, 0.90). All components contributed to the overall result.³ The data suggest that Farxiga has the potential to be a treatment for patients with HFrEF both with and without T2D.

Another pre-specified analysis presented, Effect of Treatment on the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF), examined the effects of Farxiga on heart failure related health status (symptoms, physical limitations and quality of life) in HFrEF, assessed using the KCCQ. An improvement in the KCCQ total score for dapagliflozin compared to placebo was seen at 4 months, and the magnitude of the improvement was amplified at 8 months. Furthermore, fewer patients treated with Farxiga had significant deterioration (≥5 points), and more experienced small (≥5 points), moderate (≥10 points) and large (≥15 points) clinically meaningful improvements in total KCCQ score.⁴ The total symptom score on the KCCQ range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure and a change of 5 or more points considered to be clinically meaningful.

The Timing of Onset of Clinical Benefit with Dapagliflozin in Patients with Heart Failure: An Analysis from the Dapagliflozin And Prevention of Adverse-outcomes In Heart Failure Trial (DAPA-HF) post-hoc analysis explored the timing of onset of clinical benefit with Farxiga in patients with HFrEF compared to placebo. Reduction in the risk of the composite of worsening HF or CV death versus placebo was shown as soon as 4 weeks.⁵ These exploratory data reinforce that Farxiga provides crucial early benefit for patients with HF.

The Effect of Treatment According to Age in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF) subgroup analysis suggested that Farxiga may benefit outcomes in patients with HFrEF, regardless of age. There was no apparent effect of age on the occurrence of adverse events or treatment discontinuation of dapagliflozin versus placebo.⁶

The Influence of Ejection Fraction on the Effect of Treatment in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF) subgroup analysis indicated that the treatment effects of dapagliflozin versus placebo were consistent over a broad spectrum of left ventricular ejection fraction (LVEF) (P interaction = 0.205 for primary composite outcome). LVEF is a predictor of mortality and hospitalisation related to HF.⁷

These positive Farxiga results build on the DAPA-HF detailed results announced in September 2019. Farxiga is currently being studied in patients with heart failure with preserved ejection fraction (HFpEF) in the DELIVER and DETERMINE (HFrEF and HFpEF) trials.

Additionally, in September 2019, the US Food and Drug Administration (FDA) granted Fast Track designation for Farxiga to reduce the risk of CV death, or the worsening of HF in adults with HFrEF or HFpEF based on the Phase III DAPA-HF and DELIVER trials. The US FDA also recently updated the Farxiga label to reduce the risk of hospitalisation for heart failure (hHF) in adults with T2D and established CVD or multiple CV risk factors. The approval was based on results from the landmark DECLARE-TIMI 58 CV outcomes trial (CVOT), the largest SGLT-2 inhibitors CVOT conducted to date.

About DAPA-HF

DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multi-centre, parallel group, randomised, double-blind trial in patients with heart failure and reduced ejection fraction (LVEF ≤ 40%), with and without T2D, designed to evaluate the effect of Farxiga 10mg, compared with placebo, given once daily in addition to standard of care. The primary composite outcome was timed to a worsening heart failure event (hospitalisation or equivalent event; i.e. an urgent heart failure visit), or cardiovascular death.

The full results of the DAPA-HF trial were published in The New England Journal of Medicine in September 2019.

About Farxiga

Farxiga is a first-in-class, oral once-daily SGLT2 inhibitor indicated as both monotherapy and as part of combination therapy to improve glycaemic control, with the additional benefits of weight loss and blood-pressure reduction, as an adjunct to diet and exercise in adults with T2D. Farxiga has a robust programme of clinical trials that 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.

About AstraZeneca in CVRM

Cardiovascular, Renal & Metabolism (CVRM) together forms one of AstraZeneca’s three therapy 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 to protect organs and improve 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 cardiovascular health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal and Metabolism, and Respiratory. 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.      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.

2.      Mozaffarian D et al. Circulation. 2016 Jan 26;133(4):e38-360 and the CDC. Retrieved from https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm.

3.      McMurray, John. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF – Results in nondiabetic patients. Presented at: American Heart Association (AHA) Scientific Sessions 2019, 16 Nov – 17 Nov, Philadelphia, USA.

4.      Kosiborod, Mikhail N. Effect of treatment on the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF) Presented at: American Heart Association (AHA) Scientific Sessions 2019, 16 Nov – 17 Nov, Philadelphia, USA.

5.      Sabatine, Marc S. Timing of Onset of Clinical Benefit with Dapagliflozin in Patients with Heart Failure: An Analysis from the Dapagliflozin And Prevention of Adverse-outcomes In Heart Failure Trial (DAPA-HF). Presented at: American Heart Association (AHA) Scientific Sessions 2019, 16 Nov – 17 Nov, Philadelphia, USA.

6.      Martinez, Felipe. Effect of treatment according to age in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF). Presented at: American Heart Association (AHA) Scientific Sessions 2019, 16 Nov – 17 Nov, Philadelphia, USA.

7.      Solomon, Scott. Influence of ejection fraction on the effect of treatment in the Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure Trial (DAPA-HF). Presented at: American Heart Association (AHA) Scientific Sessions 2019, 16 Nov – 17 Nov, Philadelphia, USA.