The Landmark DECLARE-TIMI 58 Cardiovascular Outcomes Trial of FARXIGA in Patients with Type 2 Diabetes to Be Featured at AHA 2018

New data on cardiovascular effects of long-term BRILINTA use in patients with a history of heart attack

Data from 20 abstracts further highlight AstraZeneca's holistic approach to care in cardiovascular, renal and metabolic diseases

AstraZeneca will present 20 abstracts including a late-breaking oral presentation on the full results from the Phase III cardiovascular (CV) outcomes trial (CVOT) DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58, the broadest SGLT2 inhibitor CVOT conducted to date, as well as new research from the Company's Cardiovascular, Renal & Metabolism (CVMD) therapy area at the American Heart Association (AHA) Scientific Sessions, November 10-12, 2018, in Chicago, Illinois, USA.

New evidence will build on broad clinical research from AstraZeneca that aims to help redefine the management of CVMD diseases and address the need for a more proactive and holistic approach to patient care. Presentations will include findings from some of the largest trials in broad patient populations with FARXIGA (dapagliflozin) in type 2 diabetes (T2D), BRILINTA (ticagrelor) in patients with a history of heart attack, and in hyperkalemia.

Danilo Verge, Vice President, Cardiovascular, Renal & Metabolism, Global Medical Affairs, said: "An estimated 20 million people each year die from cardiovascular, renal and metabolic diseases, yet shared risk factors are frequently not diagnosed or addressed holistically.^1,2,3 Our data at AHA reflect an integrated approach to managing the needs of patients living with type 2 diabetes and risk of cardiovascular or renal disease, and those with a history of cardiovascular disease at acute and long-term risk of recurrence. We stand firmly behind our mission to provide new solutions earlier in disease management to these patients at risk for multiple complications."

DECLARE-TIMI 58: a landmark CVOT evaluating CV risk in patients with T2D

Clinical trial results showing the safety and efficacy of FARXIGA vs. placebo on primary CV and secondary renal efficacy outcomes in adults with T2D who have multiple CV risk factors or established CV disease, will be presented in a late-breaking oral presentation (Late Breaking Abstract #19485). DECLARE-TIMI 58 evaluated the CV outcomes of FARXIGA vs. placebo over a period of up to five years, across 33 countries and in more than 17,000 adults with T2D with multiple CV risk factors or established CV disease.

In September 2018, AstraZeneca announced that FARXIGA met its primary safety endpoint of non-inferiority for major adverse cardiovascular events (MACE) and achieved a statistically-significant reduction in the composite endpoint of hospitalization for heart failure (hHF) or CV death, one of the two primary efficacy endpoints. Additionally, fewer MACE events were observed with FARXIGA for the other primary efficacy endpoint, however, this did not reach statistical significance. Clinical trial results presented at AHA Scientific Sessions 2018 will include additional details on the primary CV safety and efficacy, as well as secondary renal efficacy outcomes from DECLARE-TIMI 58. FARXIGA is not indicated to reduce the risk of CV events, hHF or renal outcomes.

Three new sub-analyses from the PEGASUS-TIMI 54 trial will also be presented. The trial compared BRILINTA (90mg or 60mg twice daily) plus aspirin vs. aspirin alone in 21,162 patients with prior (1 to 3 years) heart attack. The sub-analyses evaluate:

• Whether clinical characteristics predicting bleeding and ischemic risk identify subgroups of patients who may derive benefit from long-term treatment with BRILINTA, with a lower risk of major bleeding (Poster #Sa2100)
• The effects of long-term use of BRILINTA in patients who have had a heart attack and who did not receive a coronary stent vs. those who did receive a coronary stent placement (Oral Presentation #102)
• The use of high-sensitivity cardiac troponin to identify patients who are at a higher-risk of major CV events (Oral Presentation #100)

Data will also be presented on potential risk factors for repeated or persistent hyperkalemia (Poster # SuMDP65).

Key abstracts at the AHA Scientific Sessions 2018:

The full list of scientific data can be accessed on the AHA 2018 Online Planner here. You can also follow us live during the event on Twitter and LinkedIn.

INDICATION AND LIMITATIONS OF USE FOR FARXIGA (dapagliflozin) tablets 5 mg and 10 mg

FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. 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
• Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
  FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended in patients with an eGFR persistently between 30 and <60 mL/min/1.73 m²
• 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 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
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
• Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

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 read US Full Prescribing Information and Medication Guide for FARXIGA

IMPORTANT SAFETY INFORMATION FOR BRILINTA (ticagrelor) 60-MG AND 90-MG TABLETS

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. BLEEDING RISK

• BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
• Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

• Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

• Dyspnea was reported in about 14% of patients treated with BRILINTA, more frequently than in patients treated with control agents. Dyspnea resulting from BRILINTA is often self-limiting
• Discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
• Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients

ADVERSE REACTIONS

• The most common adverse reactions associated with the use of BRILINTA included bleeding and dyspnea: In PLATO, for BRILINTA vs clopidogrel, non-CABG PLATO-defined major bleeding (3.9% vs 3.3%) and dyspnea (14% vs 8%); in PEGASUS, BRILINTA vs aspirin alone, TIMI Total Major bleeding (1.7% vs 0.8%) and dyspnea (14% vs 6%)

DRUG INTERACTIONS

• Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
• As with other oral P2Y₁₂ inhibitors, coadministration of opioid agonists delay and reduce the absorption of ticagrelor. Consider use of a parenteral anti-platelet in ACS patients requiring co-administration
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
• Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

INDICATIONS FOR BRILINTA

BRILINTA is indicated to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

DOSING

In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

Patients can find out more information about BRILINTA at www.BRILINTA.com or by calling 1-888-412-7454.

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1-800-FDA-1088.

NOTES TO EDITORS

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVMD)

Cardiovascular, renal and metabolic diseases together form one of AstraZeneca's main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney 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. Our ambition is to modify or halt the natural course of CVMD diseases and even 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 commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit http://www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. World Health Organization. Cardiovascular Disease: World Heart Day 2017 Accessed October 29, 2018. http://www.who.int/cardiovascular_diseases/world-heart-day-2017/en/.

2. Wang H et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet 2016; 388(10053):1459–544. https://doi.org/10.1016/S0140-6736(16)31012-1.

3. Ogurtsova K et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128:40–50. https://doi.org/10.1016/j.diabres.2017.03.024.

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