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

Abstract

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 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.

Keywords: Antiplatelet drugs; Antithrombotic drugs; Artificial intelligence drug modelling; BMI; Cardiovascular diseases; Drug variability; Obesity; Obesity classes; Underweight.

Graphical Abstract

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.

Figure 1

Scale and symbols representing the strength of advice statements, based on evidence and consensus of the writing group, as recommended for the European Society of Cardiology scientific documents.

Figure 2

Antithrombotic drugs can be affected by marked changes in body size in each step of their pharmacokinetics, i.e. absorption, distribution, metabolism, and excretion. Underweight is commonly associated with comorbidities, reduced renal function, and changes in plasma proteins. Severe obesity is associated with relevant changes in the gastrointestinal tract, body size composition (fat vs. lean mass ratio and plasma proteins), kidney, and liver functions, including the activity of the cytochrome P450 enzymes, which can impact drug absorption, distribution, biotransformation, and excretion. Bariatric surgery by inducing anatomical modifications in the gastrointestinal tract and metabolic changes can also influence each step of drug pharmacokinetics. Data post-bariatric surgery refer mainly to Roux-en-Y gastric bypass surgery. **Oral liquid formulations should not contain non-absorbable sugars due to dumping syndrome risk; open capsules if allowed according to the summary of product characteristics. Based on Angeles et al., Krogstad et al., Kvitne et al.,^, and Sandvik et al. BMI, body mass index; Cmax, peak plasma concentrations; CYP, cytochrome P450; FFA, free fatty acids; GFR, glomerular filtration rate; LBT, lean body tissue; LBW, lean body weight; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; P-gp, P-glycoprotein; s.c., subcutaneous; t1/2, elimination half-life; TBW, total body weight; Tmax, time to reach Cmax; UDPGT, uridine diphosphate glycosyltransferase enzymes; Vd, volume of distribution.

Figure 3

Relevant steps in managing morbidly obese individuals who have one or more ongoing indication(s) for antithrombotic drugs and undergo bariatric surgery and some relevant points to be checked and considered before and immediately after bariatric surgery and at long-term afterwards, providing that the indication for one or more antithrombotic drug (both for treatment and prophylaxis) persists. BMI, body mass index; BW, body weight; (D)OAC, (direct) oral anticoagulant; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonists.