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Antiplatelet therapy has a critical role to play in the successful management of patients undergoing percutaneous coronary intervention (PCI). Over the past 40 years, a multitude of participants worldwide have been enrolled in trials evaluating the impact of antiplatelet agents on clinical outcomes. The use of aspirin in unstable angina in the Canadian Aspirin trial was key to establishing the benefit of aspirin in acute coronary syndrome. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated that the P2Y12 inhibitor clopidogrel, when added to aspirin, reduced major cardiovascular events. While the use of antiplatelet agents in coronary artery disease antedates the introduction of PCI and remains the cornerstone of secondary prevention of atherosclerotic cardiovascular disease, strategies aiming to optimise their best use are still constantly evolving. In this review, the major randomised trials shaping current clinical practice for the use of aspirin and P2Y12 inhibitors in patients undergoing PCI are summarised, with a focus on aspirin-free strategies and on the role of P2Y12 inhibitor treatment before PCI, two major topics of ongoing investigation that are critical to patient care but that are not addressed in current practice guidelines. Multiple questions remain regarding the use of antiplatelet agents after PCI, including the personalisation of dosing, intensity, pharmacologic formulation, and duration of antiplatelet therapy based on individual patient characteristics and the optimal treatment of patients at high bleeding risk.

The use of the antiplatelet agent aspirin (acetylsalicylic acid) was previously routinely recommended for the primary prevention of cardiovascular (CV) events in patients with diabetes, but recent large-scale randomized trials have failed to demonstrate a sizeable net clinical benefit with a once-daily, low-dose (81–100 mg) regimen in this population. Previous pharmacokinetic and pharmacodynamic studies have suggested that the aspirin formulation (enteric-coated) and dosing schedule (once daily) studied in randomized trials for primary prevention of CV events defining contemporary clinical practice may not leverage the full potential of the drug, particularly in patients with diabetes. Indeed, the diabetic platelets bear characteristics that increase their thrombotic potential and alter their pharmacologic response to the drug. Consequently, the appropriateness of studying a uniform aspirin regimen in landmark primary prevention trials needs to be revisited. In this review, we present the evidence showing that diabetes not only increases baseline platelet reactivity, but also alters platelet response to aspirin through different mechanisms including a faster platelet turnover rate. Obesity, which is frequently associated with diabetes, also impacts its pharmacokinetics via an increase in distribution volume. Small-scale pharmacokinetic and pharmacodynamic studies have suggested that the relative aspirin resistance phenotype observed in patients with diabetes may be reversed with a twice-daily dosing schedule, and with nonenteric-coated aspirin formulations. Properly powered randomized controlled trials investigating the efficacy and safety of aspirin dosing schedules and formulations tailored to the population of patients with diabetes are urgently required to optimize patient care.

Adequate dosing of antimicrobials is critical to properly treat infections and limit development of resistance and adverse effects. Limited guidance exists for antimicrobial dosing adjustments in patients requiring extracorporporeal membrane oxygenation (ECMO) therapy. A systematic review was conducted to delineate the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in critically ill adult patients requiring ECMO. Medline, EMBASE, Global Health, and All EBM Reviews databases were searched. Grey literature was examined. All studies reporting PK/PD parameters of antimicrobials in critically ill adults treated with ECMO were included, except for case reports and congress abstracts. Ex vivo studies were included. Two independent reviewers applied the inclusion and exclusion criteria. Reviewers were then paired to independently abstract data and evaluate methodological quality of studies using the ROBINS-I tool and the compliance with ClinPK guidelines. Patients’ and studies’ characteristics, key PK/PD findings, details of ECMO circuits and co-treatments were summarized qualitatively. Dosing recommendations were formulated based on data from controlled studies. Thirty-two clinical studies were included; most were observational and uncontrolled. Fourteen ex vivo studies were analysed. Information on patient characteristics and co-treatments was often missing. The effect of ECMO on PK/PD parameters of antimicrobials varied depending on the studied drugs. Few dosing recommendations could be formulated given the lack of good quality data. Limited data exist on the PK/PD of antimicrobials during ECMO therapy. Rigorously designed and well powered populational PK studies are required to establish empiric dosing guidelines for antimicrobials in patients requiring ECMO support. CRD42018099992 (Registered: July 24th 2018).

The long-term residual risks for cardiovascular (CV) events among individuals taking statins for primary prevention remain unclear. Our objective was to determine the long-term rates and predictors of CV interventions (CVI) and CV events (CVE) in statin users for primary CV prevention. The