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. Author manuscript; available in PMC: 2018 May 1.
Published in final edited form as: Am J Med. 2017 Feb 1;130(5):517–524. doi: 10.1016/j.amjmed.2016.12.033

Oral Anticoagulant Use after Bariatric Surgery: A Literature Review and Clinical Guidance

Karlyn A Martin *, Craig R Lee †, Timothy M Farrell ‡, Stephan Moll **
PMCID: PMC5401640  NIHMSID: NIHMS848386  PMID: 28159600

Abstract

Bariatric surgery may alter the absorption, distribution, metabolism and/or elimination (disposition) of orally administered drugs via changes to the gastrointestinal tract anatomy, body weight, and adipose tissue composition. As some patients who have undergone bariatric surgery will need therapeutic anticoagulation for various indications, appropriate knowledge is needed regarding anticoagulant drug disposition and resulting efficacy and safety in this population. We review general considerations about oral drug disposition in patients after bariatric surgery, as well as existing literature on oral anticoagulation after bariatric surgery. Overall, available evidence on therapeutic anticoagulation is very limited and individual drug studies are necessary to learn how to safely and effectively use the direct oral anticoagulants. Given the sparsity of presently available data, it appears most prudent to use warfarin with INR monitoring, and not direct oral anticoagulants, when full-dose anticoagulation is needed after bariatric surgery.

INTRODUCTION

As the prevalence of extreme obesity, defined as a body mass index (BMI) of greater than or equal to 40 kg/m2, continues to rise worldwide, so, too, does the number of bariatric procedures performed: in the United States alone, an estimated 200,000 bariatric surgeries are performed annually 1, 2. Clinicians therefore must make management decisions on people who have undergone bariatric surgeries. One such decision is managing therapeutic anticoagulation, because inappropriate anticoagulant drug levels can have serious consequences: thromboembolism if levels are too low, or bleeding if levels are too high. In the absence of dedicated studies of oral anticoagulation use after bariatric surgery, clinicians must consider how bariatric surgery affects the absorption and pharmacokinetics of, and hence the efficacy and safety of, oral anticoagulant agents. Herein, we review the available literature on how bariatric surgery affects the disposition of oral anticoagulant agents, and discuss considerations for managing patients who have had bariatric surgery and need therapeutic anticoagulation.

TYPES OF BARIATRIC SURGERY

The term “bariatric surgery” comprises multiple procedures, including adjustable gastric banding (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and biliopancreatic diversion with duodenal switch (BPD-DS) (Figures 1a–d). As of 2014, sleeve gastrectomy was the most common bariatric procedure performed in the United States (51.7%), followed by RYGB (26.8%), revisions (11%), and gastric banding (9.5%) 3. Bariatric surgeries result in weight loss through 1) restriction of caloric intake by reducing the volume of the stomach, 2) malabsorption by reducing the effective intestinal surface area, or 3) a combination of restriction and malabsorption. SG and AGB are solely restrictive. In SG, a longitudinal resection of the stomach reduces its volume to approximately 60–80 mL, thereby restricting caloric intake 4, 5. In AGB, an adjustable silicone band is placed around the stomach to create a smaller pouch that similarly restricts caloric intake. RYGB and BPD-DS use a combination of restriction and malabsorption. These surgeries differ in the location and connection of the alimentary channel, the biliopancreatic channel, and the common limb. In RYGB, the stomach is stapled to form a 15–30 mL proximal gastric pouch, which is then connected to an alimentary limb of jejunum 75–150 cm distally, resulting in a modest degree of malabsorption1. In BPD-DS, the gastric volume is reduced to a lesser degree, and the gastric pouch is reattached more distally to the terminal ileum 6, which results in a much shorter common channel, a considerable reduction in the absorptive surface, and more significant malabsorption.

Figure 1.

Figure 1

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A–D: Bariatric procedures. A: Roux-en-Y gastric bypass; B: Sleeve gastrectomy; C: Gastric banding. D: Biliopancreatic diversion with duodenal switch.

INFLUENCE OF ANATOMIC CHANGES ON DRUG DISPOSITION

The anatomic changes from bariatric procedures have several physiologic effects on drug absorption and resultant bioavailability, which depend on both physiochemical properties of the drug (i.e., solubility, degree of ionization, stability, and molecular size) 7 and properties of the gastrointestinal tract (pH, blood flow, intestinal transit time, and surface area for absorption) 6, 8.

Reduced Caloric Intake

First, the restrictive nature of the procedures leads to reduced caloric intake, which may impact drugs that require food to increase bioavailability (Table 1). Therapeutic doses of rivaroxaban (15 mg and 20 mg), for example, depend on food to increase absorption:9 the area under the curve (AUC) and peak concentration (Cmax) of a 20 mg tablet of rivaroxaban increased by 39% and 76%, respectively, with co-administration of food,10 and the bioavailability of the 15 mg dose of rivaroxaban reached ≥80% when given with food 11. Thus, the absorption of therapeutic rivaroxaban may be reduced in patients placed on very restrictive diets, which can limit caloric intake to as little as 500 kcal daily after bariatric surgery. However, the bioavailability of apixaban, dabigatan, edoxaban, and warfarin do not appear to be significantly affected by co-administration of food.

Table 1.

Characteristics of oral antithrombotic

Antithrombotic
agent		 Location of
absorption		 Volume of
distribution* 		Biopharmaceutics Classification
System† 		Concurrent food intake impact
on drug absorption
Apixaban Primarily proximal
small intestine; some
gastric absorption 18,
19, 46 		21L 47
(0.3 L/kg)		 BCS Class III (high solubility, low
permeability)		 No effect
Take without regard to food
Dabigatran Lower stomach and
duodenum 21 		50-70L 48
(0.7-1 L/kg)		 BCS Class II (Low Solubility, High
Permeability)		 No effect
Take without regard to food
Edoxaban Proximal small
intestine 23 		107 L 49
(1.5 L/kg)		 BCS Class IV (low solubility, low
permeability)50 		+6-22% 51
Take without regard to food
Rivaroxaban Primarily proximal
small intestine; some
gastric absorption 9, 11 		50L
(0.7 L/kg)		 BCS Class II (Low Solubility, High
Permeability)29 		+39% 10, 11
Take 15 and 20 mg dose with
food to improve bioavailability
Warfarin Proximal 25 0.14 L/kg 52
(10 L)		 BCS Class II (Low Solubility, High
Permeability) 53 		No effect
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*

Reported values obtained from the prescribing information (calculated values based on 70 kg patient)

†

BCS class is a FDA classification system that classifies drugs based on their solubility and intestinal permeability 54

Decreased Absorptive Surface

The change in absorptive surface may alter the absorption of drugs as well. The reduced volume for gastric acid secretion leads to a more alkaline pH in the gastric pouch, which could affect pH-dependent drug dissolution and resultant absorption, particularly of drugs that are coated or in controlled-release formulation 12. Dabigatran, for example, requires an acidic environment for absorption and, therefore, is packaged in capsules containing tartaric acid 13, 14. While an approximately 20% reduction in absorption was seen when dabigatran was given with antacids, this is thought not to be clinically meaningful 15. The PK of rivaroxaban, apixaban, and edoxaban are not altered by drugs that increase gastric pH 10, 16, 17.

Surgical changes that alter the anatomy of the gastrointestinal tract may affect location of drug absorption, and in the absence of dedicated studies, indirect evidence such as the location of drug absorption (Figure 2) can be used to attempt to predict how oral anticoagulant therapy will be affected by bariatric surgery. Apixaban is absorbed primarily in the proximal small intestine, with some gastric absorption and limited colonic absorption 18–20. Rivaroxaban appears to be absorbed primarily in the stomach, as there is reduced absorption (29% decrease in AUC and 56% decrease in Cmax) when the drug is released into the proximal small intestine, with further reduction as the drug is released more distally into the small intestine and colon 9. Dabigatran is thought to be absorbed in the lower stomach and duodenum because of the rapid time to peak levels 21. Moreover, a case report showed reduced absorption in short bowel syndrome contributing to insufficient anticoagulation and drug levels below published values of therapeutic doses of dabigatran22. Edoxaban is predominately absorbed in the proximal small intestine 23. While no apparent direct studies of the location of warfarin absorption exist, it is thought to be absorbed extensively in the stomach and proximal small intestine according to several case series 24. In one report, patients had prolonged prothrombin times after jejunal and ileal bowel resection; 25 in others, patients with severe short bowel syndrome were are able to adequately absorb warfarin (presumably because stomach and duodenum are intact); and in another, a patient who underwent total gastrectomy and RYGB subsequently required much higher doses of warfarin to achieve therapeutic levels 26. One patient who had both stomach and duodenum removed, however, developed warfarin resistance 24. These case reports demonstrate that even with large GI resections, warfarin may still be well absorbed because of its high bioavailability, but that it may be difficult to achieve adequate absorption in cases with very significant resections that result in the loss of the majority of stomach and proximal small intestine. In summary, with the limitations of knowledge highlighted above, absorption of the anticoagulants appears to occur in the approximate areas outlined in Figure 2.

Figure 2.

Figure 2

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Location of absorption of anticoagulants

Other Influences

Anatomic changes that result from bariatric surgery may have additional effects on drug disposition. Motility and transit time may be increased in RYGB patients 1, and with less time for absorption, drugs theoretically may not be fully absorbed 12, 27. Further, enteric metabolism and transport proteins that play a role in the intestinal metabolism of and the efflux/influx of drugs across the intestinal wall make critical contributions to the bioavailability of numerous drugs, and surgeries that bypass the small intestine may alter these mechanisms for a particular drug, thereby affecting the drug’s bioavailability 1, 2. The direct impact of bariatric surgery on enteric metabolism and transport, however, remains unclear.

INFLUENCE OF WEIGHT AND WEIGHT LOSS ON PHARMACOKINETICS

Volume of Distribution

In addition to changes resulting from the anatomic modifications of bariatric surgery, alterations in drug PK due to both excess weight and weight loss may also occur. Volume of distribution (Vd), the extent to which a drug distributes into tissues, depends largely on lipid solubility and other physicochemical properties of the drug 28. As excess weight in obesity is comprised of adipose tissue, the Vd for lipid-soluble drugs may be higher in individuals with obesity compared to normal-weight individuals, whereas Vd may be minimally different for more water-soluble drugs 7. A reduction in total body and adipose tissue weight from dramatic weight loss may change drug disposition depending on a drugs lipophilicity and, thus, Vd.

Rivaroxaban has been reported to exhibit moderate lipophilicity, as reflected by its logP value (octanol/water partition) coefficient of 1.5 and its low-to-moderate affinity to peripheral tissues 29. The other DOACs (logP values range from 1.4 to 2.2) and warfarin (logP value of 2.7) also exhibit moderate lipophilicity 30. These physicochemical properties, coupled with their relatively low Vd in healthy subjects (Table 1) and modest associations between increasing body weight and increasing Vd in population pharmacokinetic models 31, 32, suggest that these agents likely partition to some degree into tissue (presumably adipose tissue), but largely reside within the vascular space. The clinical relevance of weight-associated changes in the Vd of these agents, however, remains unclear.

Clearance

Clearance is the principal determinant of steady-state plasma concentrations of a continuously-dosed drug. 28 It is typically mediated by the liver and/or kidney, and depends on physiological processes including blood flow and the extraction capability for a given drug. The effects of obesity on clearance are not well-defined and likely vary by drug. There is limited literature on the effects of weight loss on clearance, and whether clearance in individuals who have undergone dramatic weight loss is similar to normal-weight individuals who have not been previously obese 28. Since the extent of weight loss associated changes in drug distribution and clearance likely vary by drug, precisely predicting the effect of bariatric procedure-evoked weight loss on the PK of a specific drug requires dedicated study.

Studies on Effect of Weight on PK of DOACs

It has been demonstrated that body weight extremes can alter the pharmacokinetics of apixaban, rivaroxaban, dabigatran and edoxaban following administration of fixed doses 33. Following a single dose of apixaban in healthy subjects weighing ≤50 kg (low), 65–85 kg (normal), and ≥120 kg (high), high body weight had 30% higher clearance and 24% higher Vd 34, which translated into a 31% lower Cmax and 23% lower AUC in the high body weight group compared to the normal-weight group. In a similar study conducted with rivaroxaban, weight ≤50 kg was associated with a 24% higher Cmax and 14% higher AUC compared to weight 70–80 kg; however, weight >120 kg was not associated with significantly altered rivaroxaban exposure or Vd 35. Weight ≥100 kg is associated with 21% lower dabigatran trough (Cmin) concentration compared to patients weighing 50–100 kg 36. Edoxaban exposure in patients with very high body weight has not been reported. Therefore, the population of patients with obesity who undergo bariatric surgery may have altered drug exposure because of extreme weight. Further, given the PK relationships between drug exposure and weight, it would be reasonable to hypothesize that weight loss, particularly extreme weight loss secondary to bariatric surgery, would decrease the Vd and clearance and increase the exposure and antithrombotic effect of these agents. However, the presence, magnitude, time-course, and mechanisms mediating these effects remain unknown and will require direct investigation.

Summary of Pharmacokinetic Effects

The mechanisms that underlie these processes are complex and have not been shown to be predictable when drugs are studied individually. Indeed, a study found that using PK parameters within a biopharmaceutical classification system could not alone explain the observed variability in bioavailability after bariatric surgery 4. Therefore, the sum of the changes imparted by bariatric procedures makes it difficult, if not impossible, to accurately predict oral bioavailability – and, consequently, PK, clinical efficacy and safety – for a given drug without a dedicated study of that drug 2, 28.

CLINICAL DATA

Information from direct studies of therapeutic oral anticoagulant use after bariatric surgery is very limited and comes mostly from retrospective studies of small numbers of patients.

Vitamin K antagonists (warfarin and others)

Literature is most robust for vitamin K antagonists (VKA) compared to other oral anticoagulants. One study compared warfarin dosing in 27 patients before and after bariatric surgery (82% post- RYGB and 18% post- GB) to a matched control group of 59 patients undergoing alternative abdominal surgeries 37. A significant reduction in the median weekly dose of warfarin after bariatric surgery was found, ranging from 7.7 mg/week decrease at days 8–14 after surgery to a 30 mg/week decrease at days 50–56 (p<0.01), though the absolute change in dosing for individual patients varied substantially, ranging from 0 to 40 mg/week in the three months following surgery. Interestingly, the weekly dose requirement returned to and remained at pre-surgery doses 90–180 days post-operatively. The mechanism of reduced dose-requirements after surgery, whether by altered absorption due to anatomic changes or lower vitamin K intake, could not be determined from the study alone 38. Another retrospective study demonstrated a rise in “warfarin sensitivity” (as defined by INR >3 or the need to decrease warfarin dose) within 30 days of bariatric surgery compared to 30–150 days after surgery; notably, after 30 days post-operatively, there was a trend toward increased warfarin dose requirements 39. Additionally, a smaller study of ten patients found that the mean weekly dose of warfarin was reduced by 64% from baseline within 21 days after bariatric surgery, with dose requirements rising as time passed, reaching up to 90% of pre-surgery mean warfarin requirements at 1 year 40. Furthermore, the average time out of therapeutic range was much higher in the first week after surgery compared to weeks 2 and 3 post-operatively, and the average time out of therapeutic range decreased from weeks 4 to 6. Another small retrospective study of twelve patients also found a statistically significant reduction of warfarin dose by approximately 25% after bariatric surgery, with a median weekly warfarin dose of 37.4 mg before surgery compared to median weekly warfarin dose of 32.5 mg after surgery 41. Notably, unlike the studies discussed above, this study did not find a significant difference between warfarin doses at 1 and 6 months after surgery.

While the mechanism of reduced warfarin requirements after bariatric surgery remains unclear, it may be due in part to alterations in vitamin K intake and absorption; caloric reduction post-bariatric surgery has resulted in vitamin K deficiencies 42. Additionally, the absorption of vitamin K in the proximal intestine occurs after solubilization into micelles by bile salts and products of pancreatic lipolysis, 43 and may be affected by anatomic changes resulting from bariatric surgery.

Overall, the literature suggests that warfarin dosing is reduced in the immediate post-operative period (within 3–4 weeks), with a trend towards increased dose requirements as patients are further out from surgery. None of the studies looked at PK parameters or drug levels, however, so the mechanism underlying the observed changes remains unclear.

Direct Oral Anticoagulants

There is scant literature on the use of direct oral anticoagulants (DOACs) in the post-bariatric surgery setting. One case reported successful use of rivaroxaban following bariatric surgery: the patient started rivaroxaban 20 mg daily 2–3 months after bariatric surgery due to widely variable INRs on warfarin. Rivaroxaban anti-Xa levels measured between 3 and 24 hours after the initial dose of rivaroxaban, and again three hours after the second day’s dose, were within published ranges 44.

CLINICAL GUIDANCE

In the absence of PK/PD and clinical data on the efficacy and safety of DOACs after the various bariatric procedures, and the lack of widely available tests and clearly defined therapeutic ranges for DOACs, it is difficult to justify their use after bariatric surgery. As warfarin’s anticoagulant effect can be routinely monitored, this seems to be the preferred agent to use in patients after bariatric surgery until more data on DOACs become available. Therefore, our approach to management of oral anticoagulation in patients after bariatric surgery is as follows:

  1. We recommend using vitamin K antagonists, rather than DOACs, in patients who require full-dose anticoagulation after bariatric surgery, as VKAs can be monitored with the INR. We recommend against using DOACs, because published data describing DOAC absorption, PK/PD and clinical efficacy and safety are too sparse, and there is no PK/PD model to predict DOAC drug disposition and action in patients after bariatric surgery.

  2. If DOACs are used in a patient after bariatric surgery, we suggest checking a drug-specific peak and trough level. If the level falls within the expected published ranges 45, continuation of the DOAC seems reasonable. However, if the drug-specific level is found to be below or above the expected range, we suggest changing to a VKA rather than adjusting the dose of the DOAC. As food intake and weight may change in the weeks and months after the surgery, repeat DOAC drug level testing may be indicated at certain intervals.

CONCLUSION

There is little literature available on the effects of bariatric surgery on therapeutic anticoagulation. Drug disposition depends on food volume, pH, transit time, gastrointestinal absorptive surface, and location of drug absorption, which may all affect PK and bioavailability of an ingested drug. The changes to drug disposition after bariatric surgery are not predictable without independent study of individual drugs. The limited clinical literature that exists on therapeutic anticoagulation after bariatric surgery relates to warfarin, and suggests lower dose requirements within the first month after surgery, with rising requirements as time from surgery increases. There is scant literature on DOACs. At present, it appears most prudent to use a vitamin K antagonist rather than a DOAC for therapeutic oral anticoagulation after bariatric surgery, as the VKAs can be easily monitored and dose-adjusted.

Clinical Significance.

  • -

    changes in pharmacokinetics and bioavailability of an ingested drug after bariatric surgery are not predictable without dedicated study of individual drugs

  • -

    limited literature exists on therapeutic warfarin after bariatric surgery and even less on direct oral anticoagulants after bariatric surgery

  • -

    in the absence of dedicated studies, we suggest vitamin K antagonist as the oral anticoagulant of choice after bariatric surgery given its ability to be monitored and dose-adjusted

Acknowledgments

This work was supported by National Institutes of Health National Heart, Lung, and Blood institute T32 HL007149 (K.M.). The authors would like to thank Joe Chovan, medical illustrator (Cincinnati, OH), for the creation of the figures in this article.

ABBREVIATIONS

AUC

area under the curve

AGB

adjustable gastric banding

Cmax

peak concentration

Cmin

trough concentration

DOAC

Direct oral anticoagulants

DPD-DS

biliopancreatic diversion with duodenal switch

INR

international normalized ratio

PK

pharmacokinetics

RYGB

Roux-en-Y gastric bypass

SG

sleeve gastrectomy

Vd

volume of distribution

VKA

vitamin K antagonist

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Authorship: All authors were involved in the study design, the writing of the manuscript, and have seen and approved the submitted version.

Conflict of interest: SM has consulted for Boehringer-Ingelheim and Janssen Pharmaceuticals.

References

  • 1.Smith A, Henriksen B, Cohen A. Pharmacokinetic considerations in Roux-en-Y gastric bypass patients. Am J Health Syst Pharm. 2011;68:2241–2247. doi: 10.2146/ajhp100630. [DOI] [PubMed] [Google Scholar]
  • 2.Edwards A, Ensom MH. Pharmacokinetic effects of bariatric surgery. Ann Pharmacother. 2012;46:130–136. doi: 10.1345/aph.1Q414. [DOI] [PubMed] [Google Scholar]
  • 3.Ponce J, Nguyen NT, Hutter M, Sudan R, Morton JM. American Society for Metabolic and Bariatric Surgery estimation of bariatric surgery procedures in the United States, 2011–2014. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2015;11:1199–1200. doi: 10.1016/j.soard.2015.08.496. [DOI] [PubMed] [Google Scholar]
  • 4.Darwich AS, Henderson K, Burgin A, et al. Trends in oral drug bioavailability following bariatric surgery: examining the variable extent of impact on exposure of different drug classes. British journal of clinical pharmacology. 2012;74:774–787. doi: 10.1111/j.1365-2125.2012.04284.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Schneider BE, Mun EC. Surgical management of morbid obesity. Diabetes care. 2005;28:475–480. doi: 10.2337/diacare.28.2.475. [DOI] [PubMed] [Google Scholar]
  • 6.Miller AD, Smith KM. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm. 2006;63:1852–1857. doi: 10.2146/ajhp060033. [DOI] [PubMed] [Google Scholar]
  • 7.Macgregor AM, Boggs L. Drug Distribution in Obesity and following Bariatric Surgery: A Literature Review. Obes Surg. 1996;6:17–27. doi: 10.1381/096089296765557222. [DOI] [PubMed] [Google Scholar]
  • 8.De Smet J, Van Bocxlaer J, Boussery K. The influence of bypass procedures and other anatomical changes in the gastrointestinal tract on the oral bioavailability of drugs. Journal of clinical pharmacology. 2013;53:361–376. doi: 10.1002/jcph.65. [DOI] [PubMed] [Google Scholar]
  • 9.Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants-reasons, methods and current limitations. J Thromb Thrombolysis. 2013;36:187–194. doi: 10.1007/s11239-013-0907-y. [DOI] [PubMed] [Google Scholar]
  • 10.Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. Journal of clinical pharmacology. 2006;46:549–558. doi: 10.1177/0091270006286904. [DOI] [PubMed] [Google Scholar]
  • 11.Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. International journal of clinical pharmacology and therapeutics. 2013;51:549–561. doi: 10.5414/CP201812. [DOI] [PubMed] [Google Scholar]
  • 12.Yska JP, van der Linde S, Tapper VV, et al. Influence of bariatric surgery on the use and pharmacokinetics of some major drug classes. Obes Surg. 2013;23:819–825. doi: 10.1007/s11695-013-0882-6. [DOI] [PubMed] [Google Scholar]
  • 13.DeWald TA, Becker RC. The pharmacology of novel oral anticoagulants. J Thromb Thrombolysis. 2014;37:217–233. doi: 10.1007/s11239-013-0967-z. [DOI] [PubMed] [Google Scholar]
  • 14.Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. Journal of clinical pharmacology. 2005;45:555–563. doi: 10.1177/0091270005274550. [DOI] [PubMed] [Google Scholar]
  • 15.Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clinical pharmacokinetics. 2008;47:285–295. doi: 10.2165/00003088-200847050-00001. [DOI] [PubMed] [Google Scholar]
  • 16.Upreti VV, Song Y, Wang J, et al. Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Clinical pharmacology : advances and applications. 2013;5:59–66. doi: 10.2147/CPAA.S41999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Mendell JLK, Shi M. Effect of esomeprazole on edoxaban pharmacokinetics and pharmacodynamics when administered orally as tablet and as solution. Europace. 2011;13 Abstract P1052. [Google Scholar]
  • 18.Frost C. Assessment of the sites of gastrointestinal absorption of apixaban in healthy subjects. Clinic Pharmacol Drug Dev. 2013;2(supp 1):p19. abstract 1703161. [Google Scholar]
  • 19.Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clinical pharmacokinetics. 2009;48:1–22. doi: 10.2165/0003088-200948010-00001. [DOI] [PubMed] [Google Scholar]
  • 20.Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thrombosis journal. 2013;11:10. doi: 10.1186/1477-9560-11-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Personal communication with Dr. Joanne van Ryn N. 2015.
  • 22.Douros A, Schlemm L, Bolbrinker J, Ebinger M, Kreutz R. Insufficient anticoagulation with dabigatran in a patient with short bowel syndrome. Thrombosis and haemostasis. 2014;112:419–420. doi: 10.1160/TH14-02-0104. [DOI] [PubMed] [Google Scholar]
  • 23.Parasrampuria DA, Kanamaru T, Connor A, et al. Evaluation of regional gastrointestinal absorption of edoxaban using the enterion capsule. Journal of clinical pharmacology. 2015 doi: 10.1002/jcph.540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Brophy DF, Ford SL, Crouch MA. Warfarin resistance in a patient with short bowel syndrome. Pharmacotherapy. 1998;18:646–649. [PubMed] [Google Scholar]
  • 25.Lutomski DM, LaFrance RJ, Bower RH, Fischer JE. Warfarin absorption after massive small bowel resection. Am J Gastroenterol. 1985;80:99–102. [PubMed] [Google Scholar]
  • 26.Sobieraj DM, Wang F, Kirton OC. Warfarin resistance after total gastrectomy and Rouxen-Y esophagojejunostomy. Pharmacotherapy. 2008;28:1537–1541. doi: 10.1592/phco.28.12.1537. [DOI] [PubMed] [Google Scholar]
  • 27.Mitrov-Winkelmolen L, van Buul-Gast MW, Swank DJ, Overdiek HW, van Schaik RH, Touw DJ. The Effect of Roux-en-Y Gastric Bypass Surgery in Morbidly Obese Patients on Pharmacokinetics of (Acetyl)Salicylic Acid and Omeprazole: the ERY-PAO Study. Obes Surg. 2016 doi: 10.1007/s11695-016-2065-8. [DOI] [PubMed] [Google Scholar]
  • 28.Greenblatt HK, Greenblatt DJ. Altered drug disposition following bariatric surgery: a research challenge. Clinical pharmacokinetics. 2015;54:573–579. doi: 10.1007/s40262-015-0259-1. [DOI] [PubMed] [Google Scholar]
  • 29.Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clinical pharmacokinetics. 2014;53:1–16. doi: 10.1007/s40262-013-0100-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. [Accessed: July 5];PubChem Compound. Available from: https://www.ncbi.nlm.nih.gov/pccompound.
  • 31.Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. Journal of thrombosis and haemostasis : JTH. 2011;9:2168–2175. doi: 10.1111/j.1538-7836.2011.04498.x. [DOI] [PubMed] [Google Scholar]
  • 32.Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. Journal of clinical pharmacology. 2014;54:917–927. doi: 10.1002/jcph.288. [DOI] [PubMed] [Google Scholar]
  • 33.Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. British journal of haematology. 2011;155:137–149. doi: 10.1111/j.1365-2141.2011.08826.x. [DOI] [PubMed] [Google Scholar]
  • 34.Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. British journal of clinical pharmacology. 2013;76:908–916. doi: 10.1111/bcp.12114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. Journal of clinical pharmacology. 2007;47:218–226. doi: 10.1177/0091270006296058. [DOI] [PubMed] [Google Scholar]
  • 36.Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) Journal of the American College of Cardiology. 2014;63:321–328. doi: 10.1016/j.jacc.2013.07.104. [DOI] [PubMed] [Google Scholar]
  • 37.Irwin AN, McCool KH, Delate T, Witt DM. Assessment of warfarin dosing requirements after bariatric surgery in patients requiring long-term warfarin therapy. Pharmacotherapy. 2013;33:1175–1183. doi: 10.1002/phar.1307. [DOI] [PubMed] [Google Scholar]
  • 38.Chan LN. Warfarin dosing changes after bariatric surgery: implications on the mechanism for altered dose requirements and safety concerns--an alternative viewpoint. Pharmacotherapy. 2014;34:e26–e28. doi: 10.1002/phar.1417. [DOI] [PubMed] [Google Scholar]
  • 39.Bechtel P, Boorse R, Rovito P, Harrison TD, Hong J. Warfarin users prone to coagulopathy in first 30 days after hospital discharge from gastric bypass. Obes Surg. 2013;23:1515–1519. doi: 10.1007/s11695-013-0972-5. [DOI] [PubMed] [Google Scholar]
  • 40.Schullo-Feulner AM, Stoecker Z, Brown GA, Schneider J, Jones TA, Burnett B. Warfarin dosing after bariatric surgery: a retrospective study of 10 patients previously stable on chronic warfarin therapy. Clin Obes. 2014;4:108–115. doi: 10.1111/cob.12046. [DOI] [PubMed] [Google Scholar]
  • 41.Steffen KJ, Wonderlich JA, Erickson AL, Strawsell H, Mitchell JE, Crosby RD. Comparison of Warfarin Dosages and International Normalized Ratios Before and After Roux-en-Y Gastric Bypass Surgery. Pharmacotherapy. 2015;35:876–880. doi: 10.1002/phar.1632. [DOI] [PubMed] [Google Scholar]
  • 42.Slater GH, Ren CJ, Siegel N, et al. Serum fat-soluble vitamin deficiency and abnormal calcium metabolism after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8:48–55. doi: 10.1016/j.gassur.2003.09.020. discussion 54-45. [DOI] [PubMed] [Google Scholar]
  • 43.Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev. 1992;6:92–104. doi: 10.1016/0268-960x(92)90011-e. [DOI] [PubMed] [Google Scholar]
  • 44.Mahlmann A, Gehrisch S, Beyer-Westendorf J. Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis. 2013;36:533–535. doi: 10.1007/s11239-013-0891-2. [DOI] [PubMed] [Google Scholar]
  • 45.Samuelson BT, Cuker A. Measurement and reversal of the direct oral anticoagulants. Blood Rev. 2016 doi: 10.1016/j.blre.2016.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. [Accessed June 9];Apixaban FDA package insert. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf.
  • 47. [Accessed 18 May 2016];ELIQUIS (apixaban) tablets label- 202155s000lbl.pdf. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf.
  • 48. [Accessed 18 May 2016];Pradaxa (dabigatran) label-0225125017lbl.pdf. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022512s017lbl.pdf.
  • 49. [Accessed 18 May 2016];SAVAYSA (edoxaban) tablets label-206316lbl.pdf. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf.
  • 50.Parasrampuria DA, Truitt KE. Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa. Clinical pharmacokinetics. 2016;55:641–655. doi: 10.1007/s40262-015-0342-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. Journal of clinical pharmacology. 2011;51:687–694. doi: 10.1177/0091270010370974. [DOI] [PubMed] [Google Scholar]
  • 52. [Accessed July 11];Coumadin FDA package insert. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf.
  • 53.Benet LZ. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. Journal of pharmaceutical sciences. 2013;102:34–42. doi: 10.1002/jps.23359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. [Accessed June 9];Bipharmaceutics Classification System. Available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm128219.htm.

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