AstraZeneca (NYSE: AZN) today announced results from a post-hoc analysis of a sub-group of the PLATO study. This new analysis evaluated outcomes in 9,946 patients with non–ST-elevation acute coronary syndrome (NSTE-ACS) managed with or without in-hospital revascularization in relation to measurements at randomization of high-sensitivity troponin-T (hs-TnT), a biomarker test that may be a more sensitive indicator of ongoing heart muscle damage than previously available troponin tests. This study was presented today at the American Heart Association (AHA) Scientific Sessions in Los Angeles, CA. In the 86.3% (n= 8,587) of NSTE-ACS patients in PLATO with elevated hs-TnT, BRILINTA ® (ticagrelor) tablets reduced the composite of cardiovascular (CV) death, myocardial infarction (MI), and stroke, consistent with the results for the overall population of the PLATO study. In the 13.7% (n=1,359) patients with normal hs-TnT, the confidence intervals around the hazard ratios were broad. Because of the limited number of patients without hs-TnT elevation, uncertainties remain regarding the effects of ticagrelor versus clopidogrel on outcomes in hs-TnT normal subgroups. “Hs-TnT is an important new biomarker that provides a much better ability to identify patients with ongoing myocardial damage. This biomarker allowed identification of NSTE-ACS patients with low levels of myocardial damage that would not have been detected by previous testing,” said James Ferguson, MD, Executive Director, Medical Affairs and Strategic Development, and Vice President for Global Medical Affairs. “This analysis of PLATO shows BRILINTA reduced the rate of thrombotic CV events in those NSTE-ACS patients with elevated hs-TNT, both when managed with revascularization as well as when managed medically.” BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with ACS (unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). In PLATO, BRILINTA has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. In PLATO, 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.Bleeding rates and adverse events were not assessed in this sub-group analysis. 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. Specific findings from this post-hoc analysis include:
- Among patients with elevated hs-TnT (>14 ng/L at entry) who were revascularized in-hospital (n=5,011), event rates for the composite of CV death, MI, and stroke were 8.5% for BRILINTA vs 11.2% for clopidogrel (adjusted hazard ratio [HR], 0.76 [CI 95%, 0.63-0.91]).
- Among patients with elevated hs-TnT managed medically (n=3,576), event rates for the composite of CV death, MI, and stroke were 12.4% for BRILINTA vs 14.9% for clopidogrel (adjusted HR, 0.81 [CI 95%, 0.68-0.97]).
- Among patients with normal hs-TnT (<14 ng/L at entry) who were revascularized in-hospital, (n=346), event rates for the composite of CV death, MI, and stroke were 12.2% for BRILINTA vs 11.5% for clopidogrel (adjusted HR, 0.99 [CI 95%, 0.53-1.83]).
- The event rates (composite of CV death, MI, and stroke) were low in the 1,013 medically managed NSTE-ACS patients with normal hs-TnT: 3.1% for BRILINTA vs 2.4% for clopidogrel (adjusted HR, 1.40 [CI 95%, 0.66-2.97]).
- There was no significant interaction of treatment with hs-TnT status in patients treated with in-hospital revascularization, but there was an interaction in patients managed medically.
- 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
- 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
- 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
BRILINTA is a registered trademark of the AstraZeneca group of companies.About PLATO 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 Acute Coronary Syndrome (ACS)ACS is an umbrella term for conditions that result from insufficient blood supply to the heart muscle. These conditions include unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). The conditions are defined by ECG changes and heart muscle enzyme leakage. Non–ST-elevation acute coronary syndrome (NSTE-ACS) includes unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI); the term is usually used before heart muscle enzymes have been analyzed. About AstraZeneca AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information about AstraZeneca in the U.S. or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363). 2213200 11/12