Ticagrelor (a member of the cyclopentyltriazolopyrimidines) is an anti-platelet agent that binds reversibly rather than irreversibly with the P2Y12 platelet receptor and has a more rapid onset of action than clopidogrel. The efficacy and safety of ticagrelor were evaluated in the PLATO trial involving over 18,000 patients with ACS who were randomised to receive ticagrelor (180 mg loading dose followed by 90 mg twice daily) or clopidogrel (300 to 600 mg loading dose followed by 75 mg daily) (Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045). Treatment was started as soon as possible after hospital admission (median, 5 hours) but many patients received the drug after coronary angiography. All patients received a loading dose of aspirin (325 mg in most cases) and a maintenance dose of 75-100 mg daily for patients not undergoing stenting and up to 325 mg daily for up to six months in those who received a stent. PLATO included patients who were managed medically.
At 12 months, the composite primary end point (first event of death from vascular causes, MI, or stroke) was less commonly seen in patients treated with ticagrelor (9.8 versus 11.7 %, hazard ratio 0.84, 95% CI 0.77-0.92). Ticagrelor significantly reduced the total number of events (HR 0.86, 95% CI 0.79-0.93). Incidence of major bleeding was not different in the ticagrelor group compared with the clopidogrel group (11.6 versus 11.2 % ). Ticagrelor however was associated with a significantly higher rate of major bleeding. Of interest, subgroup analysis found a potentially clinically important interaction between treatment and region with the composite primary end point occurring more often with ticagrelor in the United States (12.6 versus 10.1%, HR 1.27, 95% CI 0.93-1.75). Among stented patients, the rate of stent thrombosis was significantly reduced with ticagrelor (2.21 versus 2.87 %; HR 0.75, 95% CI 0.59-0.95).
Cardio Debate asked Prof Albert Ferro, an International expert in platelet function and antiplatelet therapy, to comment on the recent developments associated with this novel agent.
The PLATO trial continues to be the subject of much controversy, long after its publication in 2009. To date, this remains the only substantive comparative trial of ticagrelor (Brilinta / Brilique; AstraZeneca) against clopidogrel, in patients with acute coronary syndrome (ACS) also receiving aspirin. This trial, involving more than 18,000 patients with ACS from 43 countries, showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of myocardial infarction, stroke, and cardiovascular death compared with patients taking clopidogrel. On the basis of this one trial, numerous cardiac centres across the world now use ticagrelor routinely in place of clopidogrel, especially in ACS patients (who may or may not also be undergoing percutaneous coronary intervention) judged to be at especially high risk.
However, ever since its presentation at the European Society of Cardiology meeting in 2009 and its coincident publication in the New England Journal of Medicine, it has been plagued by questions as to certain apparent inconsistencies: in particular, a trend specifically in North America towards worse outcomes in patients taking ticagrelor compared to those taking clopidogrel, and apparently better outcomes at sites where AstraZeneca was in charge of trial monitoring as compared to sites where it was not. Moreover, the number of clinical events among those taking clopidogrel was particularly high compared with other studies, with an all-cause mortality nearly twice as high as earlier studies. Based on these uncertainties, the FDA took a further two years before finally approving the drug in the US in 2011 (although it was approved in other countries earlier than this).
The latest twist comes in the form of a sealed complaint filed in US district court in the District of Columbia by Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD) under the False Claims Act, who claims that the cardiovascular events in the study “may have been manipulated” . The complaint also alleges that an initial count of clinical events suggested that the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 myocardial infarctions to the clopidogrel group.
The controversy seems set to go on, with no immediate prospect of an early resolution. In the interim, this leaves cardiologists in a difficult position, knowing whether to stick with tried and trusted (and now generic, hence cheap) clopidogrel, or to go with the much more expensive ticagrelor, in ACS; or indeed, whether to opt instead for prasugrel, which showed superiority over clopidogrel specifically in ACS patients undergoing percutaneous coronary intervention, in the TRITON-TIMI 38 trial. What is beyond doubt is that this episode illustrates very clearly the need not to rely on the result of one single trial when instigating a step change in clinical practice; and until we have further trial evidence, the claimed superiority of ticagrelor over clopidogrel must remain in doubt.