TY - JOUR
T1 - Update on antithrombotic therapy and body mass. A Clinical consensus Statement of the ESC Working Group on Cardiovascular Pharmacotherapy and the ESC Working Group on Thrombosis
AU - Gigante, Bruna
AU - Tamargo, Juan
AU - Agewall, Stefan
AU - Atar, Dan
AU - Ten Berg, Jurrien
AU - Campo, Gianluca
AU - Cerbai, Elisabetta
AU - Christersson, Christina
AU - Dobrev, Dobromir
AU - Ferdinandy, Péter
AU - Geisler, Tobias
AU - Gorog, Diana A
AU - Grove, Erik L
AU - Kaski, Juan Carlos
AU - Rubboli, Andrea
AU - Wassmann, Sven
AU - Wallen, Håkan
AU - Rocca, Bianca
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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 changes Risks 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 silico PK/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 1 and 2. LMWH, low-molecular-weight heparin; OAC, oral anticoagulation; UFH, unfractionated heparin. in 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 silico pharmacokinetic/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.
AB - 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 changes Risks 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 silico PK/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 1 and 2. LMWH, low-molecular-weight heparin; OAC, oral anticoagulation; UFH, unfractionated heparin. in 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 silico pharmacokinetic/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.
KW - Antiplatelet drugs
KW - Antithrombotic drugs
KW - Artificial intelligence drug modelling
KW - BMI
KW - Cardiovascular diseases
KW - Drug variability
KW - Obesity
KW - Obesity classes
KW - Underweight
U2 - 10.1093/ehjcvp/pvae064
DO - 10.1093/ehjcvp/pvae064
M3 - (Systematic) Review article
SN - 2055-6837
VL - 10
SP - 614
EP - 645
JO - European Heart Journal-Cardiovascular Pharmacotherapy
JF - European Heart Journal-Cardiovascular Pharmacotherapy
IS - 7
M1 - pvae064
ER -