J Thromb Thrombolysis DOI 10.1007/s11239-014-1057-6
LETTER TO THE EDITOR
Rivaroxaban use following bariatric surgery Zachariah Thomas • Yaron Bareket Wendy Bennett
•
Ó Springer Science+Business Media New York 2014
The recent case report by Dr. Mahlmann et al. [1] describing the pharmacokinetics of rivaroxaban in a bariatric surgery patient is a welcome addition to the literature. However, we feel it necessary to clarify the statement made regarding the ‘‘high bioavailability’’ of rivaroxaban and express caution regarding the use of this agent in postoperative bariatric surgery patients. The bioavailability of rivaroxaban depends on the dose and also the presence of food. Studies have shown that rivaroxaban doses up to 10 mg have high bioavailability. However, higher doses, which are employed for the prevention of stroke in atrial fibrillation and the treatment of venous thromboembolism (VTE), have poor bioavailability (*66 % for a 20 mg dose) [2, 3]. In pharmacokinetic studies, the bioavailability of higher doses is markedly improved (C80 %) when taken with food [2]. For this reason, the rivaroxaban prescribing information states that it should be taken ‘‘with food’’ for the atrial fibrillation and VTE treatment indications [4]. ‘‘With food’’ is a rather vague description with interpretations ranging from ‘‘take with a small snack’’ to ‘‘take with a full meal.’’ In the ROCKET–AF trial, patients were instructed to take their dose with their evening meal, but no specific calorie or size requirements were specified [5]. In the VTE treatment studies, patients were instructed to take their doses with meals with no further specifications [6, 7].
Z. Thomas (&) Y. Bareket W. Bennett Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA e-mail: [email protected] Z. Thomas Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
In the previously mentioned pharmacokinetic studies, ‘‘with food’’ was specifically a large meal of approximately 1,000 kcal [2]. While it is doubtful that subjects receiving rivaroxaban in clinical trials took their doses with such a large caloric intake, it seems reasonable to presume their doses were taken with standard meals and that their caloric intake was essentially normal (*1,800–2,500 kcal per day in the USA) [8]. Venous thromboembolism is a cause of morbidity and mortality after gastric bypass surgery and obesity increases the risk of atrial fibrillation [9, 10]. The relative ease of rivaroxaban compared to traditional agents may make it an attractive option for patients experiencing these events after bariatric surgery. To our knowledge, there are no clinical trial data to support the use of rivaroxaban for these indications specifically in bariatric surgery patients. Although the report by Mahlmann et al. [1] and a previous study that suggests that rivaroxaban is not influenced by extremes of weight [11] offers some reassurance, other factors must be considered before rivaroxaban is used in these patients. Specifically, we believe that patients who are in the early postoperative period after bariatric surgery should not receive rivaroxaban for either the atrial fibrillation or VTE treatment indications due to the low caloric intake (*500 calories per day) that is characteristic of the diets that these patients are placed on postoperatively [12]. In Dr. Mahlmann’s report [1], rivaroxaban was started several months after bariatric surgery and thus this patient’s caloric intake would likely have been much closer to normal relative to the postoperative period. Since the minimum amount of food required ensuring adequate absorption of rivaroxaban has not been determined, it is quite plausible that the low calorie consumption of the postoperative gastric bypass patient is insufficient to support adequate rivaroxaban absorption. Furthermore,
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decreased absorption would likely lead to reduced intensity anticoagulation. Subtherapeutic anticoagulation has been linked to poor outcomes in patients experiencing VTE and atrial fibrillation [13–15]. Given the unavailability of routine monitoring techniques for rivaroxaban and the absence of a well defined therapeutic range, until more data are available, we would advise against the use of rivaroxaban in these patients, particularly in the early postoperative period when caloric intake is minimal. We encourage the manufacturer to conduct and sponsor studies of rivaroxaban in special populations such as this.
Conflict of interest Drs. Bareket and Thomas report receiving consulting fees from Janssen Pharmaceuticals, the manufacturer of rivaroxaban.
References 1. Mahlmann A, Gehrisch S, Beyer-Westendorf J (2013) Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis 36:533–535 2. Stampfuss J, Kubitza D, Becka M, Mueck W (2013) The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 51:549–561 3. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2006) 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. J Clin Pharmacol 46:549–558 4. Xarelto Prescribing Information (2013). http://www.xareltohcp. com/sites/default/files/pdf/xarelto_0.pdf. Accessed 17 Dec 2013 5. Protocol for: Patel MR, Mahaffey KW, Garg J, et al. (2013) Rivaroxaban versus warfarin in nonvalvular atrial abrillation. N Engl J Med 2011; http://www.nejm.org/doi/suppl/10.1056/ NEJMoa1009638/suppl_file/nejmoa1009638_protocol.pdf. Accessed 17 Dec 2013
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6. Protocol for: The EINSTEIN–PE investigators (2013). Oral rivaroxaban for the treatment of symptomatic pulmonary. N Engl J Med 2012; http://www.nejm.org/doi/suppl/10.1056/NEJMoa1113572/ suppl_file/nejmoa1113572_protocol.pdf. Accessed 17 Dec 2013 7. Protocol for: The EINSTEIN investigators (2013). Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; http://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/ suppl_file/nejmoa1007903_protocol.pdf. Accessed 17 Dec 2013 8. Centers for Disease Control and Prevention (2013). National Health and Nutrition Examination Survey. Intake of calories and selected nutrients for the United States Population, 1999–2000. http://www.cdc.gov/nchs/data/nhanes/databriefs/calories.pdf. Accessed 17 Dec 2013 9. Finks JF, English WJ, Carlin AM, Krause KR, Share DA, Banerjee M, Birkmeyer JD, Birkmeyer NJ (2012) Predicting risk for venous thromboembolism with bariatric surgery: results from the Michigan Bariatric Surgery Collaborative. Ann Surg 255:1100–1104 10. Magnani JW, Hylek EM, Apovian CM (2013) Obesity begets atrial fibrillation: a contemporary summary. Circulation 128: 401–405 11. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects. J Clin Pharmacol 47:218–226 12. University of California San Francisco (2013). Dietary guidelines after bariatric surgery. http://www.ucsfhealth.org/education/diet ary_guidelines_after_gastric_bypass/. Accessed 17 Dec 2013 13. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA (1997) Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 157:2562–2568 14. Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI (2010) Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 137:1382–1390 15. Hylek EM, Skates SJ, Sheehan MA, Singer DE (1996) An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 335:540–546
LETTER TO THE EDITOR
Rivaroxaban use following bariatric surgery Zachariah Thomas • Yaron Bareket Wendy Bennett
•
Ó Springer Science+Business Media New York 2014
The recent case report by Dr. Mahlmann et al. [1] describing the pharmacokinetics of rivaroxaban in a bariatric surgery patient is a welcome addition to the literature. However, we feel it necessary to clarify the statement made regarding the ‘‘high bioavailability’’ of rivaroxaban and express caution regarding the use of this agent in postoperative bariatric surgery patients. The bioavailability of rivaroxaban depends on the dose and also the presence of food. Studies have shown that rivaroxaban doses up to 10 mg have high bioavailability. However, higher doses, which are employed for the prevention of stroke in atrial fibrillation and the treatment of venous thromboembolism (VTE), have poor bioavailability (*66 % for a 20 mg dose) [2, 3]. In pharmacokinetic studies, the bioavailability of higher doses is markedly improved (C80 %) when taken with food [2]. For this reason, the rivaroxaban prescribing information states that it should be taken ‘‘with food’’ for the atrial fibrillation and VTE treatment indications [4]. ‘‘With food’’ is a rather vague description with interpretations ranging from ‘‘take with a small snack’’ to ‘‘take with a full meal.’’ In the ROCKET–AF trial, patients were instructed to take their dose with their evening meal, but no specific calorie or size requirements were specified [5]. In the VTE treatment studies, patients were instructed to take their doses with meals with no further specifications [6, 7].
Z. Thomas (&) Y. Bareket W. Bennett Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA e-mail: [email protected] Z. Thomas Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
In the previously mentioned pharmacokinetic studies, ‘‘with food’’ was specifically a large meal of approximately 1,000 kcal [2]. While it is doubtful that subjects receiving rivaroxaban in clinical trials took their doses with such a large caloric intake, it seems reasonable to presume their doses were taken with standard meals and that their caloric intake was essentially normal (*1,800–2,500 kcal per day in the USA) [8]. Venous thromboembolism is a cause of morbidity and mortality after gastric bypass surgery and obesity increases the risk of atrial fibrillation [9, 10]. The relative ease of rivaroxaban compared to traditional agents may make it an attractive option for patients experiencing these events after bariatric surgery. To our knowledge, there are no clinical trial data to support the use of rivaroxaban for these indications specifically in bariatric surgery patients. Although the report by Mahlmann et al. [1] and a previous study that suggests that rivaroxaban is not influenced by extremes of weight [11] offers some reassurance, other factors must be considered before rivaroxaban is used in these patients. Specifically, we believe that patients who are in the early postoperative period after bariatric surgery should not receive rivaroxaban for either the atrial fibrillation or VTE treatment indications due to the low caloric intake (*500 calories per day) that is characteristic of the diets that these patients are placed on postoperatively [12]. In Dr. Mahlmann’s report [1], rivaroxaban was started several months after bariatric surgery and thus this patient’s caloric intake would likely have been much closer to normal relative to the postoperative period. Since the minimum amount of food required ensuring adequate absorption of rivaroxaban has not been determined, it is quite plausible that the low calorie consumption of the postoperative gastric bypass patient is insufficient to support adequate rivaroxaban absorption. Furthermore,
123
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decreased absorption would likely lead to reduced intensity anticoagulation. Subtherapeutic anticoagulation has been linked to poor outcomes in patients experiencing VTE and atrial fibrillation [13–15]. Given the unavailability of routine monitoring techniques for rivaroxaban and the absence of a well defined therapeutic range, until more data are available, we would advise against the use of rivaroxaban in these patients, particularly in the early postoperative period when caloric intake is minimal. We encourage the manufacturer to conduct and sponsor studies of rivaroxaban in special populations such as this.
Conflict of interest Drs. Bareket and Thomas report receiving consulting fees from Janssen Pharmaceuticals, the manufacturer of rivaroxaban.
References 1. Mahlmann A, Gehrisch S, Beyer-Westendorf J (2013) Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis 36:533–535 2. Stampfuss J, Kubitza D, Becka M, Mueck W (2013) The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 51:549–561 3. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2006) 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. J Clin Pharmacol 46:549–558 4. Xarelto Prescribing Information (2013). http://www.xareltohcp. com/sites/default/files/pdf/xarelto_0.pdf. Accessed 17 Dec 2013 5. Protocol for: Patel MR, Mahaffey KW, Garg J, et al. (2013) Rivaroxaban versus warfarin in nonvalvular atrial abrillation. N Engl J Med 2011; http://www.nejm.org/doi/suppl/10.1056/ NEJMoa1009638/suppl_file/nejmoa1009638_protocol.pdf. Accessed 17 Dec 2013
123
6. Protocol for: The EINSTEIN–PE investigators (2013). Oral rivaroxaban for the treatment of symptomatic pulmonary. N Engl J Med 2012; http://www.nejm.org/doi/suppl/10.1056/NEJMoa1113572/ suppl_file/nejmoa1113572_protocol.pdf. Accessed 17 Dec 2013 7. Protocol for: The EINSTEIN investigators (2013). Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; http://www.nejm.org/doi/suppl/10.1056/NEJMoa1007903/ suppl_file/nejmoa1007903_protocol.pdf. Accessed 17 Dec 2013 8. Centers for Disease Control and Prevention (2013). National Health and Nutrition Examination Survey. Intake of calories and selected nutrients for the United States Population, 1999–2000. http://www.cdc.gov/nchs/data/nhanes/databriefs/calories.pdf. Accessed 17 Dec 2013 9. Finks JF, English WJ, Carlin AM, Krause KR, Share DA, Banerjee M, Birkmeyer JD, Birkmeyer NJ (2012) Predicting risk for venous thromboembolism with bariatric surgery: results from the Michigan Bariatric Surgery Collaborative. Ann Surg 255:1100–1104 10. Magnani JW, Hylek EM, Apovian CM (2013) Obesity begets atrial fibrillation: a contemporary summary. Circulation 128: 401–405 11. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects. J Clin Pharmacol 47:218–226 12. University of California San Francisco (2013). Dietary guidelines after bariatric surgery. http://www.ucsfhealth.org/education/diet ary_guidelines_after_gastric_bypass/. Accessed 17 Dec 2013 13. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA (1997) Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 157:2562–2568 14. Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI (2010) Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 137:1382–1390 15. Hylek EM, Skates SJ, Sheehan MA, Singer DE (1996) An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 335:540–546
