New Drugs and Devices From 2011 – 2012 That Might Change Your Practice

Joe Lex, MD

Disclosures

Western J Emerg Med. 2013;14(6):619-628. 

In This Article

Brilinta® (Ticagrelor)

Ticagrelor reversibly inhibits the platelet 2Y12 adenosine diphosphate receptor. It is a cyclopentyltriazolopyrimidine, similar to the antiplatelet thienopyridines clopidogrel (Plavix) and prasugrel (Effient), both of which bind irreversibly to the P2Y12 receptor. All 3 drugs are used for secondary prevention of stent thrombosis, cardiovascular death, and heart attack in patients with acute coronary syndrome (ACS). Ticagrelor was approved by the FDA based on the Platelet Inhibition and Patient Outcomes (PLATO) study, which looked at 18,624 patients with ACS from 862 centers in 43 countries who had symptom onset within.

Define CrCl, CABG and PLATO as footnote of Table 2 the previous 24 hours. Unlike CURE and PCI-CURE, the two major studies evaluating clopidogrel, PLATO included patients with ST elevation myocardial infarctions (MIs). Patients without ST-segment elevation had to have 2 of the following for study inclusion: ST segment changes indicative of ischemia; a biomarker indicative of myocardial necrosis; or a "risk factor" (Table 2). Patients with ST-segment elevation had to have persistent ST-segment elevation of at least 0.1 mV in at least 2 contiguous leads or a new left bundlebranch block, plus planned primary percutaneous coronary intervention (PCI).

Exclusion criteria included high risk of bradycardia, contraindication to clopidogrel, fibrinolytic administration within 24 hours of randomization, use of a strong CYP3A4 inhibitor or inducer, and oral anticoagulant that could not be discontinued.

In PLATO, patients were randomized to ticagrelor or clopidogrel. Patients who had not been taking aspirin received a loading dose of 325 mg, followed by 75 to 100 mg once daily, or 325 mg once daily for 6 months after stent placement.

While follow-up occurred at 1, 3, 6, 9, 12, and 13 months, the primary outcome measure was a composite endpoint at 12 months of cardiovascular death, MI, or stroke (similar to the CURE trial: PCI-CURE added recurrent angina into the composite). Results are shown in Table 3.

So for every 1,000 patients treated for up to 1 year with ticagrelor instead of clopidogrel, 11 fewer will suffer cardiovascular death, 11 fewer will have a heart attack, and 9 fewer will experience stent thromboses. The 1.9% absolute reduction (NNT=53) is being touted by AstraZeneca as a "16% reduction in death, stroke, or MI," but that, of course, is a relative reduction.

In a strange finding, efficacy was lost for patients enrolled in North America (n=1814); in fact, clopidogrel proved superior to ticagrelor in reaching the primary endpoint (11.9% vs 9.6% - see Table 4). The reasons for this are unclear, but most North American patients were from the United States. U.S. patients were heavier, had more frequent co-morbidities and were more likely to undergo PCI or CABG.

In addition, the median aspirin dose was higher in the U.S. – 325 mg versus 100 mg. Does this mean there is a drug interaction between aspirin and ticagrelor, or is it just that different aspirin doses reflect differences in patient populations. A post-hoc subgroup analysis suggested that aspirin dose, not geography, is to blame for the disparate results. Ticagrelor was approved with a requirement by AstraZeneca that they conduct educational outreach to physicians to alert them to the risk of using maintenance doses of aspirin over 100 mg daily, and there is a "black box" warning in the prescribing information about appropriate aspirin dosing.

In addition to bleeding, other adverse events included dyspnea (13.8% of patients) and, in those attached to a Holter monitor, ventricular pauses of more than 3 seconds (2%). Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor, and some components of the molecular structure of ticagrelor are almost identical to those of adenosine; hence it is conceivable that metabolites of ticagrelor activate adenosine receptors. We know that adenosine induces dyspnea by bronchoconstriction, depresses the atrioventricular node, and causes deterioration in renal function by arteriolar constriction. These adverse events were generally self-limiting, but ticagrelor was discontinued because of adverse events more frequently than clopidogrel. Since less than 6% of the study patients had chronic renal disease, congestive heart failure, or obstructive pulmonary disease, we do not have good information on how these patients will fare taking ticagrelor.

Ticagrelor does not have to be metabolized to become active and thus has a faster onset than clopidogrel or prasugrel. In addition, it binds reversibly to the platelet, theoretically making it an attractive option in patients requiring surgery; nonetheless, the manufacturer recommends stopping the drug 5 days before major surgery, similar to clopidogrel.

In a striking coincidence, the average wholesale cost of the three most recent anticoagulant/antiplatelet drugs are similar (Table 5).

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