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Gina Dube, PharmD, CACP, RPh
Published Online: Thursday, June 9, 2016


OBESITY PREVALENCE
The percentage of individuals suffering from obesity in the United States has increased tremendously over the past few years. More than one-third (34.9%, or 78.6 million) of US adults are obese.1 In a study conducted by Finkelstein et al, the medical costs of obesity were estimated to be as high as $78.5 billion in 1998 and may have risen to $147 billion per year by 2008. These costs are $1429 higher per patient than those for normal-weight individuals.2

The World Health Organization and the American Medical Association recognize obesity as a chronic disease. Obesity is defined as a body mass index (BMI) of 30 kg/m2 or higher. BMI is the measurement of body fat content based on body weight and height. Obesity leads to various medical conditions, such as heart disease, stroke, type 2 diabetes, and certain types of cancer—all of which are leading causes of preventable death.1 The high prevalence of obesity is contributing to the rising need for bariatric surgery.

THE INDICATION FOR BARIATRIC SURGERY
Bariatric surgery is indicated in individuals with a BMI greater than 40 kg/m2 or greater than 35 kg/m2 plus 1 or more significant comorbid conditions.3 It is also indicated when less invasive methods of weight loss have failed and the patient is at risk for obesity- associated morbidity and mortality.3 Bariatric surgery causes weight loss via restriction (limiting the amount of food the stomach can hold, thus limiting the calories the patient can eat) and/or malabsorption (shortening or bypassing part of the small intestine, thus reducing the amount of calories and nutrients the body absorbs).

The most common types of bariatric surgeries are Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric binding, sleeve gastrectomy, and duodenal biliopancreatic diversion.4 The benefits of this surgery include significant weight loss, as well as improvements in quality of life, psychological functioning, and comorbid conditions. The risks associated with this surgery include intra-abdominal infection, hemorrhage, dumping syndrome, venous thromboembolism, and nutrition and protein deficiencies.3

MECHANISM OF WARFARIN AFTER BARIATRIC SURGERY
Bariatric surgery also causes drug malabsorption. The mechanisms of malabsorption include reduced surface area for drug absorption, decreased length of intestine and drug transit time, changes in pH affecting drug dissolution, and the bypass of drug transporter locations.4 Overall, the changes in medication absorption are substantially due to alteration of drug pharmacokinetics secondary to anatomic changes. The reduction of stomach size also leads to a decrease in absorption time, which leads to lower drug bioavailability.5

Warfarin (Coumadin) is one of the drugs shown to be affected by changes resulting from bariatric surgery. Warfarin produces its anticoagulation effects by blocking vitamin K-dependent synthesis of clotting factors II, VII, IX, and X, and proteins C and S. Drugs comparable to warfarin are predominantly absorbed in the proximal jejunum and ileum.6 Thus, anatomic changes from surgery can affect warfarin absorption. Warfarin is also a weak acid with a pKa of 5.05 and is predominantly un-ionized at normal stomach pH.4 Changes in stomach pH after surgery could also lead to changes in absorption.

In addition, patients who have undergone RYGB are prone to nutrient deficiencies of fat-soluble vitamins. Vitamin K deficiency may lead to a reduction in vitamin K-dependent clotting factors, thereby affecting the dosage requirements for warfarin.4 These patients also have a significant reduction in dietary vitamin K intake after surgery because their diet consists of clear liquids for the first few days, with a gradual switch to pureed and soft foods for a few weeks.

READMISSION RATE OF WARFARIN USERS VERSUS NONUSERS
The need for warfarin dosage adjustments after bariatric surgery has been illustrated in a number of cohort studies. In a study conducted by Bechtel et al, 30-day readmission rates for warfarin users were compared with those of nonwarfarin users over a 3-year period. Overall, 10% of the entire population was readmitted for bleeding symptoms.7 Most bleeding complications occurred in the laparoscopic RYGB group. In the study, the mean international normalized ratio (INR) for more than 10 days after surgery was 5.8. It has been suggested that the observed elevation in INR and increased sensitivity to warfarin are due primarily to reduced gastric acid and drug absorption.7

CONCLUSION
Long-term warfarin patients require a postoperative dose reduction of ≥20%, especially for RYGB procedures.8 The mechanism by which sensitivity to warfarin occurs is still unknown; however, it has been suggested that the reduction of the intestinal surface area in patients who have undergone this procedure may decrease the absorption of warfarin.4 Health care professionals need to be proactive and work collaboratively when preparing a patient for bariatric surgery. Close monitoring of postop INR is required to prevent superfluous complications. Further clinical trials are needed to investigate the overall mechanism by which patients who undergo bariatric surgery become sensitized to warfarin.


Dr. Dube is an advanced practice clinical pharmacist at the Anticoagulation Management Service at Brigham and Women’s Hospital. She also serves as a preceptor to pharmacy students at the hospital.


References

  1. Adult obesity facts. CDC website. cdc.gov/obesity/data/adult.html. Accessed March 25, 2016.
  2. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff (Millwood). 2009;28(5):w822-w831. doi: 10.1377/hlthaff.28.5.w822.
  3. Guidelines for clinical application of laparoscopic bariatric surgery. Society of American Gastrointestinal and Endoscopic Surgeons website. sages.org/publications/guidelines/guidelines-for-clinical-application-of-laparoscopic-bariatric-surgery. Published March 25, 2008. Accessed April 25, 2016.
  4. Smith A, Henriksen B, Cohen A. Pharmacokinetic considerations in Roux-en-Y gastric bypass patients. Am J Health Syst Pharm. 2011;68(23):2241-2247. doi: 10.2146/ajhp100630.
  5. Miller A, Smith KM. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm. 2006;63(19):1852-1857.
  6. Heber D, Greenway FL, Kaplan LM, Livingston E, Salvador J, Still C; Endocrine Society. Endocrine and nutritional management of the post-bariatric surgery patient: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(11):4823-4843. doi: 10.1210/jc.2009-2128.
  7. Betchel 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(10):1515-1519. doi: 10.1007/s11695-013-0972-5.
  8. 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(11):1175-1183. doi: 10.1002/phar.1307.