Evaluation of the Efficacy of Oral Anticoagulants in Patients Who Have Undergone Bariatric Surgery

| June 1, 2020

by ABRAHAM Z. CHELOFF, MS

Mr. Cheloff is a medical student at Harvard Medical School in Boston, Massachusetts.

Funding: No funding was provided for this article.

Disclosures: The author reports no conflicts of interest relevant to the content of this article.

Abstract: As the number of bariatric procedures performed in the United States each year continues to rise, a greater proportion of the physician workforce will need to be knowledgeable regarding how to medically manage these patients. One decision physicians might often face when treating this patient population is choosing the best anticoagulant, because these patients could potentially be on oral anticoagulation for many years after surgery. In this review, we assess the currently available literature on how bariatric surgeries affect the absorption and distribution of common oral anticoagulants, including vitamin K antagonists and direct-acting oral anticoagulants. Current data most robustly support the use of vitamin K antagonists, such as warfarin, in patients who have undergone bariatric procedures. Though there is emerging experience with direct-acting oral anticoagulants, caution is advised given that laboratory monitoring has not been validated with respect to clinical outcomes nor are assays widely available.

Keywords: Bariatric surgery, anticoagulation, vitamin K, fibrinolytic agents, warfarin

Column editor: Daniel B. Jones, MD, MS, FASMBS
Professor of Surgery, Harvard Medical School, Vice Chair, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Bariatric Times. 2020;17(6):16–17.

With almost 40 percent of adults in the United States classified as having obesity and the number of bariatric procedures performed in the United States steadily increasing each year, reaching an all-time high at 252,000 procedures in 2018, clinicians across the country must be better prepared to make management decisions in patients who have undergone such operations.1,2 Obesity and abdominal surgery can both increase the risk for thrombotic complications, which in turn can increase the risk of pulmonary embolism, deep vein thrombosis (DVT), and portal-splenic-mesenteric venous thrombosis—a combined incidence of which is up to three percent 4 and 70 to 80 percent occurring postdischarge.4 Additionally, as obesity increases a patient’s risk for atrial fibrillation by 49 percent, three percent of patients undergoing bariatric surgery are on chronic anticoagulation before surgery.5,6 For these reasons, anticoagulation is often indicated not only in the immediate postoperative period, but chronically for many years afterward. One critical decision for physicians is which oral anticoagulant is the best to use in this population. Because bariatric surgery can have consequences for the pharmacokinetics of medications, standard dosing could lead to thromboembolic events or bleeding. Here, we will review the available literature on how bariatric surgery affects the pharmacokinetics of oral anticoagulants and what considerations are needed when prescribing these medications for patients who have had bariatric procedures performed.

Pharmacokinetic Change after Bariatric Surgery

All bariatric surgeries lead to anatomic and physiologic changes, which can lead to effects on drug absorption and total bioavailability. The final effects depend on multiple factors, including the drugs’ intrinsic properties (i.e., size, polarity, solubility) and the changes to the gastrointestinal tract, including pH and total absorption surface area.7,8 The specific bariatric surgery performed in combination with the specific drug of interest will present clinicians with a unique combination of factors that will determine the degree of absorption. Furthermore, both the initial excess weight and the subsequent weight loss can impact drug bioavailability due to changes in volume of distribution, clearance, and other pharmacokinetic parameters.9 This is all to say that due to the various and often unpredictable changes during and following bariatric surgery, it would be difficult to accurately predict the efficacy and safety for a given drug in combination with a particular surgery without dedicated studies to each.

Vitamin K Antagonists

Vitamin K antagonists (VKA) have been the mainstay for oral anticoagulation and are currently the best anticoagulant option for patients having undergone bariatric surgery. Warfarin efficacy and safety is assessed in patients though regular measurement of the International Normalized Ratio (INR), with a therapeutic range of 2.0 to 3.0 for most indications.10 A study published in 2013 assessed whether there was a difference in warfarin dosing between 27 patients who had undergone bariatric surgery (82% Roux-en-Y gastric bypass [RYGB] and 18% adjustable gastric banding [AGB]) and controls who had undergone a cholecystectomy or endoscopic retrograde cholangiopancreatography (ERCP) in a retrospective, matched-cohort study. Analysis found a significant reduction in the weekly warfarin dose for patients 8 to 90 days postbariatric surgery. There was a 7.7mg/week dose decrease at 8 to 14 days post-surgery with up to a 30mg/week decrease at 50 to 56 days postsurgery.11 Additional retrospective studies have found similar trends.5,12,13 Ultimately, the weekly dose requirement returned to baseline at 91 to 180 days postsurgery. Of note, subgroup analysis showed a significant decrease in dose for patients who had RYGB, with no significant decrease for the patients having undergone AGB.11

Though the mechanism of this reduced warfarin requirement could not be determined from this study alone,14 this sub-analysis suggests that changes in absorption might be more important than the restrictive component of bariatric surgeries. Weight loss after RYGB is due to decreased caloric absorption secondary to decreased absorption of fat. This can lead to decreased levels of fat soluble vitamins, including vitamin K,15 thereby decreasing the required dose of vitamin K antagonist, such as warfarin, to reach therapeutic levels. Overall, the current literature suggests that the dose of warfarin should be reduced in the immediate postoperative period in patients undergoing malabsorptive bariatric procedures, with a subsequent increase as patients continue through their recovery; these changes must be done with regular measurements of the INR.

Direct-acting Oral Anticoagulants

While warfarin has been the backbone in anticoagulation for more than 50 years, they have a narrow therapeutic window with the need for regular INR monitoring. Direct-acting oral anticoagulants (DOACs) with more predictable pharmacokinetics and dosing are now available, which do not require laboratory monitoring in most individuals.16

There are currently five DOACs—rivaroxaban, apixaban, edoxaban, and betrixaban, which are factor Xa inhibitors, and dabigatran, a thrombin inhibitor.17 However, guidance from the International Society of Thrombosis and Haemostasis did not recommend the use of DOACs in patients with body weights greater than 120kg due to insufficient data in such patients and a concern for underdosing in this population.18 However, several recent retrospective cohort studies suggest that DOACs might provide similar safety and efficacy to warfarin in patients with obesity19 and morbid obesity.20 The literature is scarce on the effects of bariatric surgery on the pharmacokinetic profiles of DOACs, with most publications being single-case studies. A retrospective cohort-matched study published in 2018 examined 18 postbariatric surgery patients (66% sleeve gastrectomy [SG], 22% AGB, and 11% RYGB) on various DOACs and performed DOAC blood level testing to these patients and to 18 matched controls. While the sample size was small, the investigators found that patients on apixaban (n=9) and dabigatran (n=2) had peak blood levels in the expected range, while 71 percent of patients on rivaroxaban (n=7) had levels below the expected range. Most patients that had levels below the expected range had undergone SG, while one underwent AGB.21

While this study did not seek to explain the pharmacokinetic mechanism leading to the low levels of rivaroxaban, the manufacturer states that the main site of absorption for rivaroxaban is in the stomach. Moreover, rivaroxaban’s absorption is highly dependent on the ingestion of food, and so the decreased surface area of the stomach combined with the decreased caloric intake post-gastrectomy might explain these findings.22 These results are consistent with previous data that showed a 56-percent decrease in rivaroxaban level when released directly into the proximal small intestine, leading the manufacturer to recommend that rivaroxaban not be administered distal to the stomach. Although this preliminary study has several limitations, such as a small sample size and incomplete understanding of the drug’s absorption and pharmacodynamics, it does raise concern regarding the prescription of DOACs, especially rivaroxaban, in patients following bariatric surgery.

Conclusion

Overall, while vitamin K antagonists require laboratory monitoring and individualized dosing, they are currently the best-supported method of providing oral anticoagulation to patients having undergone bariatric surgery. Preliminary data suggests that the pharmacokinetic profile of most DOACs are not altered significantly by bariatric surgery. However, without a better understanding of the effects of bariatric procedures on DOAC absorption and distribution and validated monitoring strategies for these drugs, they should be used with caution in patients with morbid obesity before and after bariatric surgery. Further studies will need to determine the efficacy of each DOAC for individual bariatric procedures and the potential need for laboratory testing to assess their efficacy and safety.

References

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