DOI: 10.25934/pr00007875
title: P2Y12 inhibitor or Aspirin moNoTHERapy as secondary prevention in patients with coronary artery disease: in individual patient data meta-analysis (PANTHER collaborative initiative)

description: The use of aspirin has its roots in history. In fact, medicines obtained from willow and other salicylate-rich plants were already used at the time of ancient Sumer and Egypt. The modern formula of aspirin, known as acetylsalicylic acid (ASA), was synthetized for the first time by the chemist Charles Frédéric Gerhardt in 1853. More than one and a half century later, ASA is one of the most prescribed medications worldwide, especially after its antiplatelet effect was discovered in the 1970s. At doses of 75 to 100 mg, ASA exerts its antithrombotic properties through the inhibition of the platelet cyclooxygenase-1 and blockade of thromboxane-A2 generation. These effects translate into clinical benefits that have made ASA the cornerstone of pharmacological therapies for cardiovascular disease and cardioembolic stroke prevention. In turn, over the past decades, most of the new antithrombotic treatment strategies aimed at further outcomes improvement have been developed manly with ASA as a background therapy. In current guidelines, ASA is class I of recommendation for secondary prevention of atherothrombotic and thromboembolic events across multiple presentations of cardiovascular disease, including coronary artery disease. 
Despite the undisputed benefits of ASA therapy, its paradigm as the cornerstone of secondary prevention has recently been questioned.
Given of the central role of platelet P2Y12 receptor signalling on coronary thrombotic complications, both spontaneous or after coronary stent implantation, there is a renewed interest in assessing the comparative effectiveness of aspirin versus currently available oral P2Y12 inhibitors, including ticlopidine, clopidogrel, ticagrelor or prasugrel as long-term secondary prevention measure in patients with established coronary artery disease. 
Our hypothesis is that an oral P2Y12 inhibitor may provide greater protection from recurrent ischemic or fatal events as compared to aspirin monotherapy without a higher incidence of side effects, in particular bleeding complications and in particular gastrointestinal bleeding complications. If this will be confirmed by our meta-analysis, these findings will have widespread clinical implications, especially considering that gastrointestinal bleeding complications are by far the most frequent side effect of aspirin in real world as shown repeatedly by multiple registry data and clinical trials. 
We will perform a systematic review and individual patient data meta-analysis of all randomised trials that compared an oral P2Y12 inhibitor (e.g. ticlopidine, clopidogrel, ticagrelor or prasugrel) monotherapy versus current standard of care consisting of aspirin among patients with established coronary artery disease. To qualify for inclusion, trials had to report centrally adjudicated outcome data, including non-fatal ischemic and bleeding events and cause of death.
Randomized trials were identified by a search in Ovid Medline, EMBASE, and three websites (www.tctmd.com, www.escardio.org, www.cardiosource.com).
Six randomised studies qualified for the analysis, including:
 
•	Clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE), 
•	Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB), 
•	Ticagrelor versus aspirin in patients after coronary-artery bypass grafting: the (TiCAB) Study, 
•	Global Leaders Adjudication Sub-Study (GLASSY), 
•	Clopidogrel and Aspirin: Determination of the Effects on Thrombogenicity (CADET)
•	Ticlopidine Versus Aspirin After Myocardial Infarction (STAMI) Trial

Our individual patient data meta-analysis will provide unique findings to inform the community, regulators and guidelines with respect to the comparative effectiveness of a secondary prevention measure performed either with aspirin monotherapy (current standard of care) or an oral P2Y12 inhibitor monotherapy treatment strategy in patients with established coronary artery disease.