Sunday, 30 August 2009
EFFICACY RESULTS ACHIEVED WITH NO INCREASE IN MAJOR BLEEDING
AstraZeneca today announced results from the phase III head to head trial, PLATO (A Study of Platelet Inhibition and Patient Outcomes), which demonstrate that ticagrelor (BRILINTA™) has achieved greater efficacy in the primary endpoint, reduction of cardiovascular events (CV death, MI, stroke) over clopidogrel (Plavix®/Iscover®) (9.8% vs. 11.7% at 12 months; 16% RRR; 95% CI, 0.77 to 0.92; p<0.001), without an increase in major bleeding (11.6% vs. 11.2%, p=0.43). This efficacy endpoint was driven by a statistically significant reduction in both CV death (4.0% vs. 5.1%, p=0.001) and heart attacks (myocardial infarction, MI) (5.8% vs. 6.9%, p=0.005) with no difference in stroke (1.5% vs. 1.3%, p=0.22). Ticagrelor is the first investigational antiplatelet that has demonstrated a reduction in CV death versus clopidogrel in patients with acute coronary syndromes (ACS). Primary results from the PLATO study were presented today at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine (NEJM), www.nejm.com.
For patients in the PLATO study, the reduction in risk of cardiovascular events with ticagrelor occurred early and this benefit increased over time compared to clopidogrel. Ticagrelor demonstrated a consistent positive effect across multiple secondary efficacy endpoints including CV death (and separately for all-cause mortality); myocardial infarction; the composite of myocardial infarction, stroke, and all-cause mortality. Among patients who received a stent during the study, a 33% reduction in risk of definite stent thrombosis was achieved with ticagrelor.
“The goal of new antiplatelet therapies is to improve the efficacy for patients without increasing the associated risks of treatment such as bleeding. Ticagrelor achieved a significant reduction in CV mortality in ACS patients versus clopidogrel and importantly without an increase in major bleeding,” commented Professor Lars Wallentin, co-chair of the PLATO Executive Committee, Uppsala Clinical Research Centre.
AstraZeneca Executive Vice-President Development, Anders Ekblom said, “The PLATO study was designed to reflect how patients with ACS are currently managed in clinical practice, by including patients who underwent invasive procedures and those who were managed with medication only. The PLATO data suggest ticagrelor could be a valuable new option for a broad range of acute coronary syndromes patients. We look forward to filing BRILINTA with regulatory authorities in the fourth quarter.”
The PLATO study confirmed the clinical safety profile of previous ticagrelor studies which showed no difference in major bleeding compared to clopidogrel. When PLATO minor bleeding was added to the major bleeding results, ticagrelor showed an increase versus clopidogrel (16.1% vs. 14.6%, p=0.008). There was also an increase in non-procedural related bleeding with ticagrelor. Within the patient subgroups of gender, weight, history of stroke/TIA, ticagrelor showed no increase in the incidence of major bleeding versus clopidogrel.
Consistent with phase II data, ventricular pauses (slowing of heart rhythms) occurred more often with ticagrelor but without associated symptoms or clinical consequences for the patient. Dyspnoea was reported more frequently by patients on ticagrelor (13.8% vs. 7.8%, p<0.001) but did not represent new or worsening heart failure or lung disease. Only one in 100 ticagrelor patients overall stopped taking study medication due to dyspnoea.
PLATO analysed 66 subgroups (33 efficacy and 33 safety subgroups). Thirty of the 33 efficacy subgroups analysed were consistent with the analysis of efficacy in the overall population; showing a benefit for ticagrelor over clopidogrel. Of the three remaining subgroups, one (patients with weight below the gender-specific median) showed an attenuated benefit for ticagrelor over clopidogrel. The other two subgroups (patients not taking a statin medication on the day of randomisation and those at sites in North America) showed no treatment advantage for ticagrelor.
Of the 33 safety subgroups analysed, 32 were consistent with the analysis of safety in the overall population; showing no statistically significant difference between ticagrelor and clopidogrel. The remaining subgroup (patients with a Body Mass Index BMI >30kg/m2) had major bleeding more frequently with ticagrelor than with clopidogrel.
Given the large number of tests performed these differences may have been due to chance. The observed difference in results between patients in North America and those enrolled elsewhere raises questions of whether geographic differences between populations of patients or practice patterns influenced the effects of the randomised treatments, although no apparent explanations have been found to date.
“As a cardiology community, we are constantly seeking rigorously studied options to offer our patients who are facing an increased risk of serious, and potentially deadly, complications," said Robert A. Harrington, M.D, co-chair of the PLATO Executive Committee, Duke Clinical Research Institute. “An estimated one in three ACS patients will die, have a recurrent heart attack or be readmitted to hospital within six months of their first cardiovascular event, so preventing reoccurrence is vital in ACS patient treatment.”
The PLATO results have confirmed AstraZeneca’s intention to submit the NDA and MAA with regulatory agencies during the fourth quarter of this year.
PLATO was a head-to-head 18,624 patient outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel plus aspirin, and was designed to establish whether ticagrelor could achieve meaningful cardiovascular and safety endpoints in ACS patients. Given the size of the PLATO database, we will continue to analyse and publish additional PLATO findings.
NOTES TO EDITORS:
Primary results from the PLATO study were presented today at the European Society of Cardiology annual meeting in Barcelona, Spain and simultaneously published in the online version of the New England Journal of Medicine (NEJM), www.nejm.com.
Ticagrelor (BRILINTA™) is an investigational oral antiplatelet treatment for ACS. BRILINTA (ticagrelor) is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events.
BRILINTA™ is the first in a new chemical class, the CPTPs (cyclo-pentyl-triazolo-pyrimidines) and is chemically distinct from the thienopyridines, such as clopidogrel and prasugrel.
AstraZeneca has proposed the name BRILINTA™. If approved by the FDA and the EMEA, it will serve as the trade name for ticagrelor. BRILINTA™ is a trademark of the AstraZeneca group of companies.
About the PLATO study
PLATO was an international head-to-head outcomes study of ticagrelor plus aspirin, versus clopidogrel plus aspirin. The PLATO study was designed to establish whether ticagrelor could achieve clinically meaningful cardiovascular and safety endpoints in ACS patients, above and beyond those afforded by clopidogrel, an irreversible therapy in the thienopyridine class of medicines.
The study design of PLATO was published in the April 2009 edition of the American Heart Journal.
PLATO Bleeding Definitions:
The bleeding definitions used within the PLATO trial were an evolution from the CURE bleeding definitions and were developed by the PLATO Executive Committee as constituting the most appropriate and clinically meaningful assessment of bleeding complications associated with acute and chronic therapy. The PLATO bleeding definitions provide a framework to allow investigators to record all bleeding events reported by patients in the PLATO trial. The bleeding definitions were developed to characterise bleeding in both the acute and long-term setting.
PLATO Secondary Endpoints Results:
CV death (4.0% vs. 5.1%, p=0.001); Separately for all-cause mortality (4.5% vs. 5.9% with clopidogrel; p<0.001); myocardial infarction (5.8% vs. 6.9%, p=0.005); the composite of myocardial infarction, stroke, and all-cause mortality (10.2% vs. 12.3%, p<0.001); and a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, recurrent cardiac ischemia, severe recurrent cardiac ischemia, and other arterial thrombotic events (14.6% vs. 16.7%, p<0.001).
AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US$ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: www.astrazeneca.com
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