New Data Suggests Ticagrelor (Brilinta®) Reduced First and Recurrent Cardiovascular and Ischemic Events

PLATO sub-analysis on the effects of BRILINTA versus clopidogrel for second events, including urgent revascularization, recurrent ischemia, transient ischemic attacks and arterial thromboses in patients with ACS

CHICAGO, Ill. — March 25, 2012 — AstraZeneca announced new data from a sub-analysis of the PLATO study that suggests that ticagrelor (Brilinta®) tablets resulted in a reduction in hazard for time to first events, recurrent cardiovascular (CV) and ischemic events, when compared to clopidogrel. These data were presented today by Dr. Payal Kohli of the TIMI Study Group and Brigham and Women’s Hospital, at the American College of Cardiology Scientific Sessions (ACC), in Chicago, Ill.

“The understanding of the impact of antiplatelet therapy on recurrent and total events is important for clinicians,” said Dr. Christopher Cannon, Professor of Medicine, Harvard Medical School. “We usually just count the first event in the trials, but looking at the total number of events reduced — we see more events reduced with ticagrelor vs. clopidogrel. These new data suggest that treatment with ticagrelor for up to one year reduced hazard for time to first and recurrent events, including cardiovascular death.”

Specific data from this sub-analysis showed:

• Ticagrelor as compared with clopidogrel reduced total events, i.e., first and second events: cardiovascular CV death, myocardial infarction (MI), stroke, severe recurrent ischemia (SRI), recurrent ischemia (RI), transient ischemic attack (TIA), arterial thrombotic events (ATE) were for ticagrelor n=2,030 (1,290 first events, 740 recurrent events) versus clopidogrel n=2,290 (1,456 first events, 834 recurrent events); (rate ratio 0.88; [95% CI; 0.80-0.98]; P=0.01). The rate ratio for total number of primary endpoints was reduced with ticagrelor compared to clopidogrel; CV death, MI, stroke (RR 0.86; [0.79-0.93]; P<0.001)

• Ticagrelor also reduced hazard for time to second event/death for CV death, MI, stroke (HR 0.80; [0.70-0.90]; P<0.001); CV death, MI, stroke, SRI, RI, TIA, ATE (HR 0.83; [0.75-0.91]; P<0.001); CV death, MI, stroke, urgent revascularization (HR 0.80; [0.71-0.91]; P<0.001)

• With respect to safety endpoints, there was an increase with ticagrelor in total number of TIMI major non-CABG bleeds, as compared to clopidogrel (234 vs. 188); P=0.03; Although first occurrences of bleeding increased with ticagrelor (221 vs. 177); P=0.03; recurrent bleeding events were rare in both groups (13 vs. 11); P=0.69

In PLATO, 18,624 patients with ACS were randomized to ticagrelor versus clopidogrel with median follow-up of 277 days. Among patients taking ticagrelor, there was a mean number of 1,057 total primary endpoint events versus 1,225 in patients on clopidogrel (rate ratio=0.86 [0.79-0.93]; P<0.001). There was an observed reduction in mean number of events per patient, and a reduction in second occurrences of CV death, MI or stroke with ticagrelor and a reduction for first, second and total ischemic events.

Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS (unstable angina [UA] non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). Ticagrelor has been shown to reduce the rate of a combined end point of CV death, 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), Ticagrelor reduces the rate of stent thrombosis.

Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

The PLATO Trial
The PLATO trial was a large (18,624 patients in 43 countries) head-to-head outcomes study of ticagrelor versus clopidogrel, both given in combination with aspirin and other standard therapy, designed to establish whether ticagrelor could achieve a clinically meaningful reduction in cardiovascular end points in ACS patients, above and beyond those afforded by clopidogrel.

The PLATO study demonstrated that treatment with ticagrelor led to a greater reduction in the primary endpoint – 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 continue to diverge throughout the 12-month treatment period.

The PLATO study also demonstrated that treatment with ticagrelor for 12 months was associated with a 21 percent RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16 percent 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 ticagrelor and 11.2% for clopidogrel). In PLATO, non-CABG (coronary artery bypass graft) major + minor bleeding events (8.7% vs. 7%) were more common with ticagrelor versus clopidogrel. The rate of non–CABG-related major bleeding was higher for ticagrelor (4.5%) vs clopidogrel (3.8%).

In a post hoc analysis of PLATO, it was determined that more than 80 percent of patients worldwide, with approximately 40 percent of patients in the US, received low maintenance doses of aspirin (100 mg or less). Results for US and non-US patients taking ticagrelor with these low maintenance doses of aspirin were similar. As with any unplanned subset analysis, the post hoc analysis should be treated with caution. Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. The PI states that maintenance doses of aspirin above 100mg reduce the effectiveness of ticagrelor, and should be avoided. After any initial dose, ticagrelor should be used with maintenance aspirin doses of 75 mg - 100 mg per day.

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