Update on antithrombotic therapy and body mass: a clinical consensus statement of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and the European Society of Cardiology Working Group on Thrombosis

Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity, who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changesin body composition, metabolism and organ function, and altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silicopharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimizing antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology.Graphical AbstractRisks of thrombosis and bleeding, antithrombotic drug management, and supporting type of evidence across body size categories. From left to right: a causal relationship between obesity and deep vein thrombosis (DVT) risk has been suggested by Mendelian randomization studies. Generally, DVT risk linearly increases from underweight to the highest body mass index classes. Despite the low risk of underweight individuals, underweight seems to have a worse prognosis once venous thrombosis has occurred. The risk of arterial thrombosis increases from normoweight to severe obesity, while the risk associated with being underweight remains less clear, possibly mimicking a U-shaped relationship. A U-shaped relationship seems to describe the risk of major bleeding associated with body size. However, the anatomical site and type of bleeding, underlying risk factors, and prognosis differ at the two extremes. Optimizing the dosing of antithrombotic drugs both in underweight and class =2 obese individuals is supported by pharmacokinetic/pharmacodynamic (PK/PD) studies and data from post hoc analyses of randomized studies, observational, and registry data as well as by artificial intelligence simulations of in silicoPK/PD models generated by population and randomized clinical trial experimental measurements. In underweight individuals, most evidence indicates better safety of reducing the daily doses of standard, fixed-dose antithrombotic drugs, while increasing the fixed dose is suggested for those in class =2 obesity. For body weight-adjusted antithrombotic drugs, individuals with higher classes of obesity may be overdosed due to a major imbalance between lean and fat mass that has a major impact on drug PK and bioavailability. On the other hand, if capping is us-//-ed, this may result in underdosing at the upper extreme of body size. Further details are reported in the Central Tables 1and 2. LMWH, low-molecular-weight heparin; OAC, oral anticoagulation; UFH, unfractionated heparin.