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.