Date: 2015-08-31
Type of information: Presentation of results at a congress
phase:
Announcement: presentation of results at the ESC Congress 2015
Company: AstraZeneca (UK)
Product: Brilinta® (ticagrelor)
Action
mechanism: platelet aggregation inhibitor. Brilinta® (ticagrelor) is a direct-acting P2Y12 receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs). It 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 acute coronary syndrome (ACS).
Disease: secondary prevention of atherothrombotic events in patients who had experienced a heart attack
Therapeutic area: Cardiovascular diseases
Country:
Trial
details: The PEGASUS-TIMI 54 study is part of AstraZeneca’s PARTHENON programme. 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) is one of AstraZeneca’s largest ever outcomes trials with more than 21,000 patients from over 1,100 sites in 31 countries in Europe, the Americas, Africa and Australia/Asia. It was conducted in collaboration with the Thrombolysis in Myocardial Infarction (TIMI) Study Group from Brigham and Women’s Hospital (Boston, MA, USA).
Latest
news: * On August 31, 2015, AstraZeneca announced details of a sub-analysis of the PEGASUS-TIMI 54 study, assessing the effect of Brilinta® (ticagrelor) in reducing atherothrombotic events in post-heart attack patients, based on the time from withdrawal of their previous P2Y12 inhibitor antiplatelet therapy. Current European guidelines recommend that dual antiplatelet therapy is stopped 12 months after a heart attack. The PEGASUS-TIMI 54 study enrolled patients who had suffered a heart attack one to three years previously. The data, presented during a Clinical Trial Update hotline session at ESC Congress 2015, demonstrated that withdrawal from P2Y12 inhibitor antiplatelet therapy is associated with heightened risk of ischaemic events, including cardiovascular death, myocardial infarction or stroke. Patients enrolled into the placebo arm of the PEGASUS-TIMI 54 study who had recently discontinued previous P2Y12 inhibitor antiplatelet therapy (within 30 days) were at heightened risk of developing a subsequent ischaemic event, compared to those who had stopped therapy over 30 days previously, regardless of the time since their original heart attack. This may be due to differences in baseline characteristics (although adjusted for in this analysis) as well as exposing continued risk by the withdrawal of therapy. Those patients randomised into the ticagrelor arms of the study within 30 days of withdrawal of therapy experienced a 27% reduction in the risk of developing a subsequent event. The benefit of treatment with ticagrelor had the greatest effect in this group, with the effect on risk decreasing as the length of time from last dose increased [≤30 days HR 0.73, >30 days to 360 days HR 0.86, >360 days HR 1.01]. The PEGASUS-TIMI 54 study investigated the efficacy and safety of ticagrelor at both 60mg and 90mg twice daily, plus low dose aspirin, compared to placebo plus low dose aspirin, for the long-term prevention of atherothrombotic events in patients who had suffered a heart attack one to three years prior to study enrolment. The full results of the PEGASUS-TIMI 54 study were published in the New England Journal of Medicine1 in March 2015 (See below). Brilinta® is currently under review in the EU and the U.S. for use in the chronic secondary prevention of atherothrombotic events in patients who had experienced a heart attack within one to three years. * On March 14, 2015, AstraZeneca announced full results from the PEGASUS-TIMI 54 study, a large-scale outcomes trial that investigated BRILINTA® (ticagrelor) tablets plus low dose aspirin, compared to placebo plus low dose aspirin, for the chronic secondary prevention of atherothrombotic events in patients who had experienced a heart attack one to three years prior to study enrolment. Key findings: Both 90mg and 60mg study doses of ticagrelor with aspirin significantly reduced the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI) or stroke compared to placebo. As expected with an oral antiplatelet and consistent with studies in similar patient populations, TIMI Major Bleeding1, the study’s primary safety endpoint, was higher with both doses of ticagrelor plus aspirin compared to placebo plus aspirin. Importantly, the rates of intracranial haemorrhage (bleeding within the skull) and fatal bleeding were low and were similar between study groups and the placebo arm. The data were presented during the opening late-breaking clinical trial session of the American College of Cardiology’s 64th Annual Scientific Session and Expo, and also simultaneously published in the New England Journal of Medicine online. Efficacy Findings: In this trial, both study doses of ticagrelor significantly reduced the primary endpoint of CV death, MI or stroke compared to placebo. The rates at 3 years were 7.85% in the ticagrelor 90mg arm, 7.77% in the ticagrelor 60mg arm, and 9.04% in the placebo arm (Hazard Ratio (HR) for ticagrelor 90mg vs placebo 0.85, 95% CI 0.75 – 0.96, P=0.0080; HR for ticagrelor 60mg vs placebo 0.84, 95% CI 0.74 – 0.95, P=0.0043). The effect of ticagrelor on each of the components of the primary endpoint was consistent. A numerical decrease in the secondary endpoints of cardiovascular death and all cause mortality was observed, but did not reach statistical significance. In addition, the primary efficacy endpoint of both doses of ticagrelor appeared consistent across major subgroups including age, sex, index MI type (STEMI/NSTEMI), time from qualifying MI, diabetes, aspirin dose, history of percutaneous intervention (angioplasty), and geographical region. Safety Findings: As expected, TIMI Major bleeding was higher with both doses of ticagrelor compared to placebo, with rates at 3 years of 2.60% in the ticagrelor 90mg arm, 2.30% in the ticagrelor 60mg arm, and 1.06% in the placebo arm (HR for ticagrelor 90mg vs placebo 2.69, 95% CI 1.96 – 3.70, p<0.001; HR for ticagrelor 60mg vs placebo 2.32, 95% CI 1.68 – 3.21, p<0.001). However, the rates of fatal bleeding or intracranial haemorrhage were low and similar between treatment arms. Fatal bleeding rates at 3 years were 0.11% in the ticagrelor 90mg arm, 0.25% in the ticagrelor 60mg arm, and 0.26% in the placebo arm (HR for ticagrelor 90mg vs placebo 0.58, 95% CI 0.22 – 1.54, p=0.27; HR for ticagrelor 60mg vs placebo 1.00, 95% CI 0.44 – 2.27, p=1.00). Intracranial haemorrhage rates at 3 years were 0.56% in the ticagrelor 90mg arm, 0.61% in the ticagrelor 60mg arm, and 0.47% in the placebo arm (HR for ticagrelor 90mg vs placebo 1.44, 95% CI 0.83 – 2.49, p=0.19; HR for ticagrelor 60mg vs placebo 1.33, 95% CI 0.77 – 2.31, p=0.31). AstraZeneca has now submitted regulatory filings to the European Medicines Agency and the FDA. * On January 14, 2015, AstraZeneca announced that the PEGASUS-TIMI 54 study, a large scale outcomes trial involving over 21,000 patients, successfully met its primary efficacy endpoint. The study assessed Brilinta® (ticagrelor) tablets at either 60mg twice daily or 90mg twice daily plus low-dose aspirin for the secondary prevention of atherothrombotic events in patients who had experienced a heart attack one to three years prior to study start. The primary efficacy endpoint was a composite of cardiovascular (CV) death, myocardial infarction (MI) or stroke. Preliminary analysis did not reveal any unexpected safety issues. Full evaluation of the data is ongoing. The PEGASUS-TIMI 54 study investigated two different doses of ticagrelor on a background of low dose aspirin versus placebo plus low dose aspirin, in patients aged 50 and older with a history of heart attack and one additional CV risk factor1. The study was designed to better understand the management of patients more than 12 months after their heart attack, who remain at high risk for major thrombotic events. Complete results from the PEGASUS-TIMI 54 study will be submitted to a scientific meeting in 2015 and pending further analysis, AstraZeneca plans to file this data with regulatory health authorities.
