Video: Phase III Head to Head Trial Showed Ticagrelor Reduced Cardiovascular Death and Heart Attacks Over Clopidogrel in Acute C
30 August 2009 - 4:01PM
PR Newswire (US)
EFFICACY RESULTS ACHIEVED WITH NO INCREASE IN MAJOR BLEEDING
WILMINGTON, Del., Aug. 30 /PRNewswire-FirstCall/ -- AstraZeneca
(NYSE: AZN) 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(TM)) 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(1) and simultaneously published in the New
England Journal of Medicine (NEJM)(2), http://www.nejm.com/. To
view the Multimedia News Release, go to:
http://www.prnewswire.com/mnr/astrazeneca/39860/ 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 analyzed 66 subgroups (33 efficacy and 33 safety
subgroups). Thirty of the 33 efficacy subgroups analyzed 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 randomization and those at sites in
North America) showed no treatment advantage for ticagrelor. Of the
33 safety subgroups analyzed, 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.
About AstraZeneca 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:
http://www.astrazeneca.com/. 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), http://www.nejm.com/. About BRILINTA(TM)
Ticagrelor (BRILINTA(TM)) 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(TM). 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.(3) PLATO Bleeding Definitions: The bleeding
definitions used within the PLATO trial were an evolution from the
CURE(4) 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).
References 1. Comparison of Ticagrelor, the first reversible oral
P2Y12 receptor antagonist, with clopidogrel in patients with acute
coronary syndromes: results of the PLATelet inhibition and patient
Outcomes (PLATO) trial. Presentation at ESC 2009. Final Program
Number 186. 2. Wallentin L, Harrington R et al, Ticagrelor versus
Clopidogrel in Patients with Acute Coronary Syndromes.
http://www.nejm.org/ 3. James S, Akerblom A, Cannon C et al,
Comparison of ticagrelor, the first reversible oral P2Y12 receptor
antagonist, with clopidogrel in patients with acute coronary
syndromes: Rationale, design, and baseline characteristics of the
PLATelet inhibition and patient Outcomes (PLATO) trial Am Heart J
2009;157:599-605. 4. Yusuf S, Zhao F, Mehta SR, et al, for the
Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial
Investigators. N Engl J Med. 2001;345:494-502.
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