AstraZeneca to Initiate a New Study of Brilinta (ticagrelor) in Patients with PAD
EUCLID trial to compare ticagrelor to clopidogrel with respect to cardiovascular death, myocardial infarction and ischemic stroke in patients with peripheral artery disease
WILMINGTON, Del.--(BUSINESS WIRE)--Jul 17, 2012 - AstraZeneca (NYSE: AZN) today announced plans to conduct the EUCLID study, a global clinical trial involving 11,500 patients with peripheral artery disease (PAD), a condition affecting approximately 27 million people in Europe and North America.1 PAD patients are at high risk of myocardial infarction (MI), strokes, and other health complications. EUCLID is designed to evaluate cardiovascular (CV) event rate and safety in PAD patients. Ticagrelor is currently not approved for the treatment of patients with PAD.
“The global burden of PAD is such that it necessitates further research of additional treatment options that may further reduce the risk of atherothrombotic CV events and CV death,” said William Hiatt, MD, Professor of Medicine, Division of Cardiology, University of Colorado School of Medicine. “The EUCLID study is an exciting clinical trial, as it may provide further clinical evidence regarding the role oral antiplatelets can play in reducing risk for patients with PAD.”
EUCLID is a randomized, double-blind, parallel group, multi-center study evaluating the efficacy of ticagrelor (monotherapy) compared to clopidogrel (monotherapy) in reducing the primary endpoint – a composite of CV death, MI or ischemic stroke – in patients with PAD.
In the EUCLID study, symptomatic PAD patients who are 50 years of age or older will be randomized to receive either ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily. Now that plans to initiate the study have been finalized, the EUCLID steering committee will begin the process of recruiting study investigators, clinical centers, and eventually patients. Dr. Hiatt is the principal investigator for the EUCLID study, which is being conducted in partnership with the Duke Clinical Research Institute, an academic research organization affiliated with the Duke University School of Medicine, and CPC Clinical Research, an academic research organization affiliate of the University of Colorado.
Ticagrelor Clinical Program
The EUCLID study (Examining Use of tiCagreLor In paD) is part of the PARTHENON program, an AstraZeneca-funded comprehensive, long-term and evolving global research initiative designed to address unanswered questions in atherothrombotic disease, and to investigate the impact of ticagrelor on CV events and death. The current PARTHENON program is designed to include more than 51,000 patients worldwide.
“Despite therapeutic advances, cardiovascular disease remains the number one cause of death worldwide,” said Judith Hsia, MD, Executive Director Clinical Research, AstraZeneca. “The PARTHENON program is part of our commitment to understand and advance treatments for cardiovascular diseases in an effort to improve patient health. The benefit of ticagrelor on CV thrombotic events, including CV mortality, observed in patients who have had an ACS event supports continued study in other areas of cardiovascular disease.”
The first clinical study of PARTHENON was PLATO (A Study of PLATelet Inhibition and Patient Outcomes). Ongoing studies in PARTHENON will move beyond ACS, investigating the use of ticagrelor as monotherapy and in comparison to other oral antiplatelets. Results of the PARTHENON program will help clinicians better understand the science behind ticagrelor of the following studies:
- PEGASUS-TIMI 54 (PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk Patients with Prior AcUte Coronary Syndrome – Thrombolysis In Myocardial Infarction Study Group): The PEGASUS study investigates the efficacy and safety of ticagrelor in the long-term prevention of recurrent ischemic events in patients with a history of MI beyond the currently approved 12-month treatment period. PEGASUS is a randomized, double-blind, parallel-group, international, multi-center study of approximately 21,000 patients across 31 countries. Patients are being randomized to either a 90 mg dose or 60 mg dose of ticagrelor BID or placebo. In addition to assigned study drug, patients will take once-daily, concomitant aspirin therapy (75 to 100 mg).
- PHILO (PHase the International Study of TicagreLor and Clinical Outcomes in Asian ACS Patients): The PHILO study will evaluate the impact of ticagrelor versus clopidogrel, both administered in combination with low-dose aspirin, on CV outcomes in Japanese and other Asian patients with ACS and planned for PCI. PHILO is a double-blind, randomized, parallel-group, multinational, Phase III, head-to-head outcomes study of approximately 800 patients.
Information about the PARTHENON program and design of specific studies will be available at the European Society of Cardiology Congress (ESC), August 25-29, in Munich, Germany. Further studies within the PARTHENON program and updates regarding ongoing trials will be announced in due course.
BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with acute coronary syndrome (ACS: unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention (PCI), BRILINTA reduces the rate of stent thrombosis.
BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.
IMPORTANT SAFETY INFORMATION ABOUT BRILINTA
WARNING: 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 planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA
- If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events
WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
- Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg - 100 mg per day
- BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins
WARNINGS AND PRECAUTIONS
- Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor
- Premature discontinuation increases the risk of MI, stent thrombosis, and death
- Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes
- BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg
- Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy
- The most commonly observed adverse reactions associated with the use of BRILINTA vs. clopidogrel were Total Major Bleeding (11.6% vs. 11.2%) and dyspnea (14% vs. 8%)
- In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
NOTES TO EDITORS
About BRILINTA® (ticagrelor) tablets
BRILINTA is an oral antiplatelet treatment for ACS. BRILINTA is a direct-acting P2Y12 receptor antagonist in a new chemical class called cyclopentyltriazolopyrimidines (CPTPs). BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic CV events, such as a heart attack or CV death, in patients with ACS.
BRILINTA is available in 90-mg tablets to be administered with a single 180-mg oral loading dose (two 90-mg tablets) followed by a twice daily, 90-mg maintenance dose. Following an initial loading dose of aspirin, BRILINTA should be used with a maintenance dose of 75 mg - 100 mg aspirin once daily, 81-mg aspirin dose in the US.
BRILINTA is a registered trademark of the AstraZeneca group of companies.
PLATO (PLATelet Inhibition and Patient Outcomes) was a large (18,624 patients in 43 countries), head-to-head patient outcomes study of BRILINTA versus clopidogrel, both given in combination with aspirin and other standard therapy. The study was designed to establish whether BRILINTA could achieve a clinically meaningful reduction in cardiovascular (CV) events in acute coronary syndrome (ACS) patients, above and beyond that afforded by clopidogrel. Patients were treated for at least 6 months and up to 12 months.
PLATO demonstrated that treatment with BRILINTA led to a significantly greater reduction in the primary end point – a composite of CV death, MI, or stroke – compared to patients who received clopidogrel (9.8% vs 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit versus clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continued to diverge throughout the 12-month treatment period.
The PLATO study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21% RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16% RRR in MI compared to clopidogrel at 12 months (5.8% vs 6.9%; 1.1% ARR; P<0.005).
The primary safety end point in the PLATO study was Total Major Bleeding (11.6% for BRILINTA and 11.2% for clopidogrel). In PLATO, non-CABG major + minor bleeding events were more common with BRILINTA versus clopidogrel (8.7% vs 7% respectively). The rate of non–CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%).
Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients treated with clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment.
About Peripheral Artery Disease (PAD)
PAD is caused by atherosclerotic plaques that narrow the arteries in the legs and can lead to leg pain with walking. Patients with PAD have atherosclerosis in other arteries, increasing their risk of heart attack, stroke and cardiovascular death. Severe cases of PAD can also lead to critical or acute limb ischemia with unhealed sores or infections on the legs or feet, resulting in tissue death, gangrene, and ultimately amputation of the infected limb.
About Acute Coronary Syndrome (ACS)
ACS is an umbrella term for conditions that result from insufficient blood supply to the heart muscle. These conditions range from unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI).
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 Belch, J. et. al. Peripheral arterial disease – a cardiovascular time bomb. British Journal of Diabetes and Vascular Disease 2007;7: 236-239.
2 Mayo Foundation for Medical Education and Research: http://www.mayoclinic.com/health/peripheral-arterial-disease/DS00537. Accessed July 13, 2012
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Posted: July 2012