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