Lead Investigator: Marco Valgimigli, Cardiocentro Ticino, Lugano and Universita della Svizzera ltaliana (USI)
Title of Proposal Research: P2Y12 inhibitor or Aspirin moNoTHERapy as secondary prevention in patients with coronary artery disease: in individual patient data meta-analysis (PANTHER collaborative initiative)
Vivli Data Request: 7875
Funding Source: None
Potential Conflicts of Interest: Dr. Valgimigli reports personal fees from Astra Zeneca, grants and personal fees from Terumo, personal fees from Alvimedica /CID, personal fees from Abbott Vascular , personal fees from Daiichi Sankyo, personal fees from Bayer, personal fees from CoreFLOW, personal fees from IDORSIA PHARMACEUTICALS LTD, personal fees from Universitat Basel I Dept. Klinische Forschung, personal fees from Bristol Myers Squib SA, personal fees from Medscape , personal fees from Vesalio , outside the submitted work.
The present study is a purely academic research project which has not and will not be funded by any commercial organization and aims at assessing the benefits and risks of the current standard of care consisting of aspirin monotherapy versus an experimental regimen of P2y12 inhibitor monotherapy in patients with established coronary artery disease who were managed conservatively or underwent coronary revascularization by means of percutaneous coronary intervention or coronary artery bypass grafting . The present work will not be influenced or affected by any prior or current working relationship with the commercial organizations listed above.
Summary of the Proposed Research:
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.
Statistical Analysis Plan:
We have assumed the direct availability of the CAPRIE dataset (Option A) for this SAP as follows:
We will include all patients recruited in CAPRIE either because of a myocardial infarction (MI) as qualifying event or who were included because of stroke or peripheral arterial disease (PAD) as qualifying event but had a prior MI in the history. Hence, we will be selecting the CAPRIE population in whom coronary artery disease is established and we will categorize them as acute coronary syndrome (ACS) if an MI was the qualifying event or as stable coronary artery disease if an MI occurred prior to inclusion.
Baseline and procedural continuous variables will be summarized by means and standard deviations, categorical variables by counts and percentages. The pre-specified primary analysis will be based on a one-step approach to model the data from all trials simultaneously using a random-effect Cox regression model stratified by trial. Pre-specified sensitivity analyses of the primary endpoints will be based on a two-step approach using an inverse-variance random-effect model, and a DerSimonian-Laird random-effects model to combine trial-level estimates. Between-trial heterogeneity will be estimated from the two-step fixed-effect model using I2. Treatment effects will be derived as hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses will be conducted in the intention-to-treat population including all randomized patients in the group they were originally allocated to. Data will be analysed up to the longest available timepoint with protocol specified P2Y12 inhibitor monotherapy in the experimental group and aspirin in the control group.
In trials with an initial Dual Antiplatelet Therapy (DAPT) phase after randomization in both experimental and control groups, patients will be left truncated at the timepoint when the trial protocol specified the change from DAPT to P2Y12 inhibitor monotherapy in the experimental group. Sensitivity analyses will be performed including the initial DAPT phase in trials with an initial DAPT phase after randomization in both experimental and control groups
For descriptive purposes, we will plot Kaplan-Meier time-to-event curves for primary and secondary endpoints. Numbers-needed-to-treat to benefit (NNTBs) were derived from the annualized control group event rate estimated from Poisson regression and the pooled HR. Pre-specified subgroup analyses of primary endpoints will be performed according to age (<65 versus ≥65 years), sex, clinical presentation at time of percutaneous coronary intervention (PCI) (acute coronary syndrome versus stable disease), diabetes, renal failure, peripheral artery disease, bleeding risk, PCI yes or no, revascularisation yes or no, type of PY12 inhibitor mandated for the experimental group and geographic region. We will separate within-trial and across-trial interactions and based tests for subgroup-by-treatment interaction on within-trial interactions. Sensitivity analyses of the co-primary endpoint and all-cause death will be done using a multivariable Cox regression stratified by trial and adjusted for all available patient characteristics at baseline. There will be no imputation to handle missing data.
Sponsor ID: P-1633
Gragnano F, Cao D, Pirondini L, Franzone A, Kim HS, von Scheidt M, Pettersen AÅ, Zhao Q, Woodward M, Chiarito M, McFadden EP, Valgimigli M. PANTHER. P2Y12 inhibitor or aspirin monotherapy for secondary prevention of coronary events. Journal of the American College of Cardiology. 2023 Jul 11;82(2):89-105. doi: 10.1016/j.jacc.2023.04.051