Direct Acting Anticoagulants (DOACs)
In recent years, direct-acting anticoagulants (DOACs) have emerged as alternatives for vitamin K antagonists to be used for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism. Currently, four DOACs are available, of which apixaban, rivaroxaban, edoxaban are direct factor Xa inhibitors, and dabigatran is a direct thrombin inhibitor. In the general population, these drugs have a predictable pharmacokinetic profile, which enables fixed dosing without routine coagulation additional monitoring and consequently, DOACs may have a profound benefit over the vitamin K antagonists (VKAs)59. However, in patients undergoing bariatric surgery, these pharmacokinetic profiles may be aberrant. This may particularly apply to rivaroxaban of which oral absorption is linear until a dose of 15 mg, while in higher doses the bioavailability is reduced and becomes dependent on co-administration with food 59. For rivaroxaban 20-mg tablets, AUC and Cmax were reported to increase by 39% and 76% when administered with food, respectively60. Also, dabigatran, which requires an acid environment for absorption for which tartaric acid is added to the tablet, the reduced volume for gastric acid secretion leading to a more alkaline pH in the gastric pouch, may be subject to altered absorption61,62. Since all DOACs are absorbed in the first part of the gastro-intestinal tract, surgery-related changes in the absorptive surface could alter the absorption of all these drugs63.
Only limited information is available about the absorption of DOACs after bariatric surgery. Kröll et al. measured the rivaroxaban AUC after a single dose of 10 mg rivaroxaban in 12 patients with obesity one day before and three days after RYGB / SG surgery 64. In this study, no significant changes in pharmacokinetic profile were reported. In an extension study, Kröll and colleagues investigated a single dose of oral rivaroxaban of 10 mg 6 to 8 months after SG or RYGB65. While the AUC and T1/2 were not significantly altered 6-8 months after surgery, Tmax was increased after RYGB and SG, and Cmax was lower and not altered in RYGB and SG patients, respectively64,65. Given the known nonlinear absorption of rivaroxaban, it is unknown whether these results can be extrapolated to 15 or 20 mg tablets.
Röttenstreich et al. matched 18 patients who underwent bariatric surgery (12 SG, four adjustable bands, and two RYGB) to 18 obese control subjects. They were receiving DOACs (9 apixaban 5 mg BID, 7 rivaroxaban 15 mg OD and 20 mg OD and 2 dabigatran 110 mg and 150 mg BID) for atrial fibrillation, pulmonary embolism or deep vein thrombosis. The median time elapsed from surgery until study inclusion was 4.9 years. Peak concentrations were within the normal range in all apixaban and dabigatran patients; however, five of the seven patients receiving rivaroxaban had significantly lower peak concentrations than the control group 66. The authors conclude that all DOACs, particularly rivaroxaban, should be used cautiously after bariatric surgery if used at all given that VKAs can be easily monitored. In two case reports, thromboembolic events related to possible impaired dabigatran absorption have been published 67,68.
Based on the above reports, it seems that until more data on DOAC use is available, VKAs or low molecular weight heparins are to be preferred of DOACs. Measuring DOAC 69–71 or anti-Xa72,73 concentrations has been suggested when applied in special patient groups, however as there is no hard evidence on the relation between peak, trough or AUC of these measures with outcome, it seems yet too early to use TDM as guidance for DOAC use in postbariatric surgery patients. In another special patient population (i.e. children), anti-Xa measurement for monitoring of the effect of rivaroxaban was regarded as inferior compared to measurement of rivaroxaban concentration. The reasons for this conclusion, is that the anti-Xa assay result may be falsely high or low because the assay can be influenced by pre-processing procedures (e.g., blood draw technique, extended time until measurement) 74.