Pre-specified pooled analysis from Phase III trials demonstrated reduction in CV death by 14% and reduction in death from any cause by 10% in patients with heart failure irrespective of ejection fraction

First heart failure medication to demonstrate mortality benefit across the full ejection fraction range

Results being presented at the European Society of Cardiology annual meeting and simultaneously published in Nature Medicine

Today, new results from a pre-specified, patient level, pooled analysis from the Phase III DAPA-HF and DELIVER trials demonstrated mortality benefit of FARXIGA^® (dapagliflozin), compared to placebo, in patients with heart failure (HF). These results were presented at the European Society of Cardiology Congress 2022 in Barcelona, Spain and simultaneously published in Nature Medicine.¹ The reduction in risk of cardiovascular (CV) death was consistent across pre-specified subgroups and is the first analysis to demonstrate a mortality benefit with an HF medication in patients with HF across the left ventricular ejection fraction (LVEF) range.

The analysis showed that FARXIGA reduced the risk of CV death by 14% (p=0.01, absolute risk reduction [ARR] 1.5%) over the median follow-up of 22 months, death from any cause by 10% (p=0.03, ARR 1.5%), total (first and repeat) hospitalization for HF (hHF) by 29% (p < 0.001, ARR 6%), and the composite of death from CV causes, myocardial infarction, or stroke by 10% (p=0.045, ARR 1.3%), in patients with HF irrespective of LVEF.¹

Prof. John McMurray, Professor of Medical Cardiology and Deputy Director of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, UK, said: “In this patient-level meta-analysis including over 11,000 patients with heart failure across the full range of ejection fraction, dapagliflozin reduced the risk of both cardiovascular death and heart failure hospitalization. These results underpin the valuable role dapagliflozin can play in clinical practice, as we can initiate treatment right away while waiting for ejection fraction to be measured.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “Heart failure remains one of the leading causes of death worldwide with high unmet need for some 64 million people. This analysis demonstrates FARXIGA’s ability to treat patients across the full left ventricular ejection fraction spectrum and reduce the risk of cardiovascular death.”

The DAPA-HF and DELIVER Phase III trials were randomized and double-blind, comparing FARXIGA to placebo. Each trial enrolled patients with a diagnosis of HF, functional limitation, and elevated natriuretic peptides. The principal difference between the two trials was that patients with an LVEF of 40% or less were randomized in DAPA-HF and those with a LVEF greater than 40% in DELIVER.^2,3 The studies included 11,007 individuals with HF across 20 countries in each trial.

INDICATIONS AND LIMITATIONS OF USE for FARXIGA^® (dapagliflozin)

FARXIGA is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular (CV) disease or multiple CV risk factors
• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction
• to reduce the risk of sustained eGFR decline, end‑stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression

FARXIGA is not recommended for patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

FARXIGA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m². FARXIGA is likely to be ineffective in this setting based upon its mechanism of action.

FARXIGA is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. FARXIGA is not expected to be effective in these populations.

DOSING

To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control.

For all other indications, the recommended dose is 10 mg orally once daily.

IMPORTANT SAFETY INFORMATION for FARXIGA^® (dapagliflozin) 5 mg and 10 mg tablets

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Patients on dialysis

Warnings and Precautions

• Ketoacidosis in Diabetes Mellitus has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Volume Depletion: FARXIGA can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating FARXIGA in these patients, assess volume status and renal function. After initiating therapy, monitor for signs and symptoms of hypotension and renal function
• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections (UTIs) and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters
• Lactation: FARXIGA is not recommended when breastfeeding

Please see link to US Full Prescribing Information for FARXIGA.

Notes

HF

HF is a chronic, long-term condition that worsens over time.⁴ It affects nearly 64 million people globally and is associated with substantial morbidity and mortality.^5,6 Chronic HF is the leading cause of hospitalization for those over the age of 65 and represents a significant clinical and economic burden.⁷ 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%)⁸. Approximately half of all HF patients have HFmrEF or HFpEF, with few therapeutic options available.^8,9

DAPA-HF

DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) was an international, multi-centre, parallel-group, randomized, double-blinded Phase III trial in 4,744 patients with HFrEF, with and without type 2 diabetes (T2D), designed to evaluate the effect of FARXIGA 10mg, compared with placebo, given once daily in addition to standard of care (SoC) consisting of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). The primary composite endpoint was time to the first occurrence of a worsening HF event (hospitalization or equivalent event, i.e., an urgent HF visit), or CV death. The median duration of follow-up was 18.2 months.³

The secondary endpoint 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 Kansas City Cardiomyopathy Questionnaire (KCCQ).³

DELIVER

DELIVER was an international, randomized, 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 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 a sodium-glucose cotransporter 2 (SGLT2) inhibitor).² DELIVER is the largest clinical trial to date in HF patients with LVEF above 40%, with 6,263 randomized patients.²

The primary endpoint was the time to first occurrence of CV death, hHF or an urgent HF visit. The secondary endpoint includes the total number of HF events (hHF or urgent HF visit) and CV death, change from baseline in the total symptom score of the KCCQ at eight months, time to the occurrence of CV death and time to the occurrence of death from any cause.²

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.

About 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. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. 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. Nature Medicine
2. 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.
3. McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21):1995–2008.
4. Cleveland Clinic [Internet]. Heart failure; [cited 2022 Jul 14] Available from: https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure
5. 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):1211–59.
6. Mozaffarian D, et al. Heart disease and stroke statistics—2016 update. Circulation. 2016; 133(4):e38–360.
7. Azad N, et al. Management of chronic heart failure in the older population. J Geriatr Cardiol. 2014; 11(4):329–37.
8. 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. 2022;79(17):e263-421.
9. Dunlay SM, et al. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2017;14(10):591–602.

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