American Journal of Emergency Medicine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban☆ Abstract We report a case of superior mesenteric artery thrombosis after the abrupt discontinuation of rivaroxaban in a 59-year-old male patient. The initial presentation was of sudden onset abdominal pain, nausea, vomiting, diarrhea, and hematochezia in the setting of recently holding rivaroxaban anticoagulation for an atrial flutter ablative procedure. Imaging revealed thrombosis of the superior mesenteric artery and acute mesenteric ischemia requiring emergent surgical intervention for embolectomy. Upon exploratory laparotomy, the bowel was found to be viable, and an embolectomy with patch angioplasty was successful without complication. This case illustrates the need for emergency medicine clinician familiarity with this possible medication adverse event with rivaroxaban. Rivaroxaban is a direct factor Xa inhibitor and 1 of the new target specific oral anticoagulants originally approved for prevention of stroke in nonvalvular atrial fibrillation after the ROCKET-AF trial [1]. Patel et al [1] reported noninferiority to warfarin for the primary end point of stroke and systemic embolism. Of note, a nonstatistically significant increase in stroke and systemic embolism was observed in patients who broke study protocol and discontinued use of rivaroxaban when compared to warfarin. In addition, a significant increase in thromboembolic events occurred after the end of the ROCKET-AF trial and discontinuation of rivaroxaban [1]. These findings raised questions regarding a possible increased risk of thromboembolic events after abrupt discontinuation of rivaroxaban and resulted in a US Food and Drug Administration (FDA)– required boxed warning. This boxed warning recommends alternative anticoagulation after cessation of rivaroxaban to avoid potential thromboembolic events [2,3]. We present the case of a patient who presented to the emergency department (ED) with a superior mesenteric artery thrombosis after abrupt temporary discontinuation of rivaroxaban, which ultimately required surgical intervention. A 59-year-old man presented to the ED with complaints of abdominal pain, nausea, vomiting, and diarrhea. In the 6 hours preceding his visit, he reports sudden onset of severe pain after eating dinner that was localized above the navel and in a band-like distribution across the epigastrium. This was associated with nausea, multiple episodes of vomiting, and 10 episodes of diarrhea with blood. The patient denied fever, chills, chest pain, and recent travel and had never previously experienced similar symptoms. Medical history was significant only for hypertension and supraventricular tachycardias including paroxysmal atrial fibrillation and atrial ☆ Funding: We declare no source of support in the form of grants, equipment, or drugs for the work presented.
flutter for which he was anticoagulated with rivaroxaban 20 mg once daily. Eight months before presentation, the patient had undergone an unsuccessful ablative procedure with recurrence of his supraventricular tachycardia. At this time, he was initiated on rivaroxaban; he was never anticoagulated with warfarin. Three months before presentation, the patient had undergone a cardioversion with return of atrial flutter within 72 hours. Most recently, 5 days before admission, the patient had a transesophageal echocardiogram with no left atrial appendage thrombus visualized, and an atrial flutter ablation was performed. Rivaroxaban was held for a total of 4 days for the procedure, 2 days before and 2 days after the ablation. The patient resumed rivaroxaban 20 mg daily therapy 3 days before symptom onset and ED presentation. On examination, he had a normal cardiovascular rate and rhythm with a heart rate of 69 beats per minutes (maximum in the ED 76 beats per minute). The patient was slightly hypertensive with a blood pressure of 154/95 mm Hg (maximum in the ED 162/100 mm Hg). He also had a respiratory rate of 20 respirations per minute and oxygen saturation of 98% on room air and was normothermic at 36.2°C (97.2°F). He appeared to be in acute distress with mild abdominal distension and tenderness with no rebound or guarding. On rectal examination, stool was dark brown and found to be strongly guaiac positive. Initial laboratory values were hemoglobin level of 14.8 g/dL, hematocrit of 44%, platelets of 196 K/μL, prothrombin time of 12.4 seconds (reference range, 9.2-12.3), activated partial thromboplastin time of 28.7 seconds (reference range, 25.8-37.9), international normalized ratio (INR) of 1.2, and lactate of 1.9 mmol/L. Diagnostic computed tomography of the abdomen and pelvis with contrast revealed a superior mesenteric artery thrombosis with left lower quadrant small bowel wall thickening and a small amount of free fluid likely related to bowel ischemia (Figs. 1-3). A surgical consult was immediately obtained, which recommended initiation of a heparin infusion (rectal blood thought to be minor) along with emergent laparotomy and thromboembolectomy with possible bowel resection in the case of bowel ischemia. The patient went to the operating room 10 hours after the initial presentation, and upon exploration, the bowel was found to be viable and an embolectomy and patch angioplasty was completed successfully without complication. His hospitalization was uncomplicated postoperatively. The patient was subsequently transitioned from a heparin infusion to lowmolecular-weight heparin to facilitate a therapeutic bridge to warfarin for outpatient anticoagulation. After initial concerns from the ROCKET-AF trial and the subsequent US FDA boxed warning, a single clinical investigation has been reported describing the possible increased risk of stroke or thromboembolic events upon rivaroxaban discontinuation [4]. This post hoc analysis of data from the ROCKET-AF trial was completed to provide clarity regarding the risks associated with discontinuation [4]. Authors concluded that aggregate
http://dx.doi.org/10.1016/j.ajem.2015.08.053 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
2
C.B. Adams et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Fig. 3. Curved reformatted computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a curved reformatted image depicting the length of the thrombosis within the vessel.
Fig. 1. Sagittal computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a sagittal view.
thromboembolic event rates did not differ after temporary interruptions (rivaroxaban: n = 14/3734 [0.37%], warfarin: n = 17/4511 [0.38%]; P = .89) and early permanent discontinuation (rivaroxaban: n = 131/2470 [5.3%], warfarin: n = 147/2425 [6.1%]; P = .16) of assigned therapy before study termination. However, there was a statistical difference in aggregate thromboembolic event rates when comparing assigned therapy after study termination during the end-of-study transition from blinded study drug to open-label warfarin (rivaroxaban: n = 31/4587
Fig. 2. Coronal computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a coronal view.
[0.68%], warfarin: n = 14/4652 [0.30%]; P = .012). This discrepancy in event rates was determined to be due to disproportionate quality of warfarin anticoagulation. When comparing treatment groups, fewer rivaroxaban patients achieved a therapeutic INR during the follow-up period [4]. Although this post hoc analysis refutes the US FDA boxed warning, in vitro data do suggest that a possible risk may be associated with cessation of rivaroxaban anticoagulation [5]. Rivaroxaban inhibits both free factor Xa and factor Xa with its associated cofactor, factor Va, which is known as the prothrombinase complex. This complex is a major source of prothrombin activation. Investigators created an in vitro model of prothrombinase characterized by prothrombin activity and simulated abrupt rivaroxaban discontinuation. Their model suggests that a prothrombotic rebound phenomenon may be possible after rivaroxaban discontinuation due to unmasking of thrombusassociated prothrombinase as rivaroxaban plasma concentrations fall [5]. Although significant limitations exist, this in vitro investigation provides a possible physiological explanation to the rivaroxabanassociated adverse event in our patient. To our knowledge, there is 1 other published case that has been reported describing the risk associated with abrupt discontinuation of rivaroxaban. An 80-year-old man newly diagnosed with atrial fibrillation and requiring anticoagulation was placed on rivaroxaban 20 mg daily. After several months of treatment, the patient experienced diarrhea that he assumed was a side effect of the rivaroxaban. The patient self-discontinued rivaroxaban and was hospitalized 5 days later due to an ischemic stroke [6]. This patient had significant risk factors for a thromboembolic event including atrial fibrillation with a CHADS2 score of at least 3. In contrast, our patient had a CHADS2 score of 1. Although differences do exist, both patients had supraventricular arrhythmias, abruptly discontinued rivaroxaban, and experienced a thromboembolic event shortly thereafter. These events may represent the inherent thromboembolic risk associated with atrial fibrillation without anticoagulation. However, given the proximity of these thromboembolic events to rivaroxaban discontinuation, the possible risk associated with rivaroxaban cessation is concerning and should not be overlooked. Although a post hoc analysis refutes the risk associated with discontinuation of rivaroxaban, in vitro data along with a previously published
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
C.B. Adams et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
case report and our case report maintain a possible clinically significant risk. This case illustrates the importance of emergency medicine clinicians' familiarity with the risk associated with abrupt rivaroxaban discontinuation, the need for alternative anticoagulation after rivaroxaban cessation, and diagnostic tools necessary for acute management of similar patients. Christopher B. Adams PharmD Department of Pharmacy Services University of California Davis Medical Center, Sacramento, CA 95817 Corresponding author at: University of California Davis Medical Center 2315 Stockton Blvd, Sacramento, CA 95817 E-mail address: [email protected] Nicole M. Acquisto PharmD, BCPS Departments of Pharmacy and Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 Jason M. Rotoli MD Department of Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 Thomas LoStracco MD Department of Imaging Sciences University of Rochester Medical Center, Rochester, NY 14642
3
Ann R. Shamaskin MD Department of Medicine University of Rochester Medical Center, Rochester, NY 14642 Joel S. Pasternack MD, PhD Department of Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 http://dx.doi.org/10.1016/j.ajem.2015.08.053 References [1] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [2] Rivaroxaban [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. [3] United States Food and Drug Administration. XARELTO (Rivaroxaban) tablets. Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.fda.gov/downloads/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ UCM295405.pdf?utm_source=fdaSearch%26utm_medium=website%26utm_term= Rivaroxaban%20box%20warning%26utm_content=1. [Accessed November 21, 2013]. [4] Patel MR, Hellkamp AS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013;61(6):651–8. [5] Haynes LM, Orfeo T, Mann KG. Rivaroxaban delivery and reversal at a venous flow rate. Arterioscler Thromb Vasc Biol 2012;32(12):2877–83. [6] Stöllberger C, Finsterer J. Stroke and urosepsis after discontinuation of rivaroxaban. Int J Cardiol 2013;169(5):e77–8.
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban☆ Abstract We report a case of superior mesenteric artery thrombosis after the abrupt discontinuation of rivaroxaban in a 59-year-old male patient. The initial presentation was of sudden onset abdominal pain, nausea, vomiting, diarrhea, and hematochezia in the setting of recently holding rivaroxaban anticoagulation for an atrial flutter ablative procedure. Imaging revealed thrombosis of the superior mesenteric artery and acute mesenteric ischemia requiring emergent surgical intervention for embolectomy. Upon exploratory laparotomy, the bowel was found to be viable, and an embolectomy with patch angioplasty was successful without complication. This case illustrates the need for emergency medicine clinician familiarity with this possible medication adverse event with rivaroxaban. Rivaroxaban is a direct factor Xa inhibitor and 1 of the new target specific oral anticoagulants originally approved for prevention of stroke in nonvalvular atrial fibrillation after the ROCKET-AF trial [1]. Patel et al [1] reported noninferiority to warfarin for the primary end point of stroke and systemic embolism. Of note, a nonstatistically significant increase in stroke and systemic embolism was observed in patients who broke study protocol and discontinued use of rivaroxaban when compared to warfarin. In addition, a significant increase in thromboembolic events occurred after the end of the ROCKET-AF trial and discontinuation of rivaroxaban [1]. These findings raised questions regarding a possible increased risk of thromboembolic events after abrupt discontinuation of rivaroxaban and resulted in a US Food and Drug Administration (FDA)– required boxed warning. This boxed warning recommends alternative anticoagulation after cessation of rivaroxaban to avoid potential thromboembolic events [2,3]. We present the case of a patient who presented to the emergency department (ED) with a superior mesenteric artery thrombosis after abrupt temporary discontinuation of rivaroxaban, which ultimately required surgical intervention. A 59-year-old man presented to the ED with complaints of abdominal pain, nausea, vomiting, and diarrhea. In the 6 hours preceding his visit, he reports sudden onset of severe pain after eating dinner that was localized above the navel and in a band-like distribution across the epigastrium. This was associated with nausea, multiple episodes of vomiting, and 10 episodes of diarrhea with blood. The patient denied fever, chills, chest pain, and recent travel and had never previously experienced similar symptoms. Medical history was significant only for hypertension and supraventricular tachycardias including paroxysmal atrial fibrillation and atrial ☆ Funding: We declare no source of support in the form of grants, equipment, or drugs for the work presented.
flutter for which he was anticoagulated with rivaroxaban 20 mg once daily. Eight months before presentation, the patient had undergone an unsuccessful ablative procedure with recurrence of his supraventricular tachycardia. At this time, he was initiated on rivaroxaban; he was never anticoagulated with warfarin. Three months before presentation, the patient had undergone a cardioversion with return of atrial flutter within 72 hours. Most recently, 5 days before admission, the patient had a transesophageal echocardiogram with no left atrial appendage thrombus visualized, and an atrial flutter ablation was performed. Rivaroxaban was held for a total of 4 days for the procedure, 2 days before and 2 days after the ablation. The patient resumed rivaroxaban 20 mg daily therapy 3 days before symptom onset and ED presentation. On examination, he had a normal cardiovascular rate and rhythm with a heart rate of 69 beats per minutes (maximum in the ED 76 beats per minute). The patient was slightly hypertensive with a blood pressure of 154/95 mm Hg (maximum in the ED 162/100 mm Hg). He also had a respiratory rate of 20 respirations per minute and oxygen saturation of 98% on room air and was normothermic at 36.2°C (97.2°F). He appeared to be in acute distress with mild abdominal distension and tenderness with no rebound or guarding. On rectal examination, stool was dark brown and found to be strongly guaiac positive. Initial laboratory values were hemoglobin level of 14.8 g/dL, hematocrit of 44%, platelets of 196 K/μL, prothrombin time of 12.4 seconds (reference range, 9.2-12.3), activated partial thromboplastin time of 28.7 seconds (reference range, 25.8-37.9), international normalized ratio (INR) of 1.2, and lactate of 1.9 mmol/L. Diagnostic computed tomography of the abdomen and pelvis with contrast revealed a superior mesenteric artery thrombosis with left lower quadrant small bowel wall thickening and a small amount of free fluid likely related to bowel ischemia (Figs. 1-3). A surgical consult was immediately obtained, which recommended initiation of a heparin infusion (rectal blood thought to be minor) along with emergent laparotomy and thromboembolectomy with possible bowel resection in the case of bowel ischemia. The patient went to the operating room 10 hours after the initial presentation, and upon exploration, the bowel was found to be viable and an embolectomy and patch angioplasty was completed successfully without complication. His hospitalization was uncomplicated postoperatively. The patient was subsequently transitioned from a heparin infusion to lowmolecular-weight heparin to facilitate a therapeutic bridge to warfarin for outpatient anticoagulation. After initial concerns from the ROCKET-AF trial and the subsequent US FDA boxed warning, a single clinical investigation has been reported describing the possible increased risk of stroke or thromboembolic events upon rivaroxaban discontinuation [4]. This post hoc analysis of data from the ROCKET-AF trial was completed to provide clarity regarding the risks associated with discontinuation [4]. Authors concluded that aggregate
http://dx.doi.org/10.1016/j.ajem.2015.08.053 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
2
C.B. Adams et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
Fig. 3. Curved reformatted computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a curved reformatted image depicting the length of the thrombosis within the vessel.
Fig. 1. Sagittal computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a sagittal view.
thromboembolic event rates did not differ after temporary interruptions (rivaroxaban: n = 14/3734 [0.37%], warfarin: n = 17/4511 [0.38%]; P = .89) and early permanent discontinuation (rivaroxaban: n = 131/2470 [5.3%], warfarin: n = 147/2425 [6.1%]; P = .16) of assigned therapy before study termination. However, there was a statistical difference in aggregate thromboembolic event rates when comparing assigned therapy after study termination during the end-of-study transition from blinded study drug to open-label warfarin (rivaroxaban: n = 31/4587
Fig. 2. Coronal computed tomographic image. Arrow indicating the superior mesenteric artery thrombosis using a coronal view.
[0.68%], warfarin: n = 14/4652 [0.30%]; P = .012). This discrepancy in event rates was determined to be due to disproportionate quality of warfarin anticoagulation. When comparing treatment groups, fewer rivaroxaban patients achieved a therapeutic INR during the follow-up period [4]. Although this post hoc analysis refutes the US FDA boxed warning, in vitro data do suggest that a possible risk may be associated with cessation of rivaroxaban anticoagulation [5]. Rivaroxaban inhibits both free factor Xa and factor Xa with its associated cofactor, factor Va, which is known as the prothrombinase complex. This complex is a major source of prothrombin activation. Investigators created an in vitro model of prothrombinase characterized by prothrombin activity and simulated abrupt rivaroxaban discontinuation. Their model suggests that a prothrombotic rebound phenomenon may be possible after rivaroxaban discontinuation due to unmasking of thrombusassociated prothrombinase as rivaroxaban plasma concentrations fall [5]. Although significant limitations exist, this in vitro investigation provides a possible physiological explanation to the rivaroxabanassociated adverse event in our patient. To our knowledge, there is 1 other published case that has been reported describing the risk associated with abrupt discontinuation of rivaroxaban. An 80-year-old man newly diagnosed with atrial fibrillation and requiring anticoagulation was placed on rivaroxaban 20 mg daily. After several months of treatment, the patient experienced diarrhea that he assumed was a side effect of the rivaroxaban. The patient self-discontinued rivaroxaban and was hospitalized 5 days later due to an ischemic stroke [6]. This patient had significant risk factors for a thromboembolic event including atrial fibrillation with a CHADS2 score of at least 3. In contrast, our patient had a CHADS2 score of 1. Although differences do exist, both patients had supraventricular arrhythmias, abruptly discontinued rivaroxaban, and experienced a thromboembolic event shortly thereafter. These events may represent the inherent thromboembolic risk associated with atrial fibrillation without anticoagulation. However, given the proximity of these thromboembolic events to rivaroxaban discontinuation, the possible risk associated with rivaroxaban cessation is concerning and should not be overlooked. Although a post hoc analysis refutes the risk associated with discontinuation of rivaroxaban, in vitro data along with a previously published
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
C.B. Adams et al. / American Journal of Emergency Medicine xxx (2015) xxx–xxx
case report and our case report maintain a possible clinically significant risk. This case illustrates the importance of emergency medicine clinicians' familiarity with the risk associated with abrupt rivaroxaban discontinuation, the need for alternative anticoagulation after rivaroxaban cessation, and diagnostic tools necessary for acute management of similar patients. Christopher B. Adams PharmD Department of Pharmacy Services University of California Davis Medical Center, Sacramento, CA 95817 Corresponding author at: University of California Davis Medical Center 2315 Stockton Blvd, Sacramento, CA 95817 E-mail address: [email protected] Nicole M. Acquisto PharmD, BCPS Departments of Pharmacy and Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 Jason M. Rotoli MD Department of Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 Thomas LoStracco MD Department of Imaging Sciences University of Rochester Medical Center, Rochester, NY 14642
3
Ann R. Shamaskin MD Department of Medicine University of Rochester Medical Center, Rochester, NY 14642 Joel S. Pasternack MD, PhD Department of Emergency Medicine University of Rochester Medical Center, Rochester, NY 14642 http://dx.doi.org/10.1016/j.ajem.2015.08.053 References [1] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [2] Rivaroxaban [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. [3] United States Food and Drug Administration. XARELTO (Rivaroxaban) tablets. Risk Evaluation and Mitigation Strategy (REMS). Available at: http://www.fda.gov/downloads/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ UCM295405.pdf?utm_source=fdaSearch%26utm_medium=website%26utm_term= Rivaroxaban%20box%20warning%26utm_content=1. [Accessed November 21, 2013]. [4] Patel MR, Hellkamp AS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol 2013;61(6):651–8. [5] Haynes LM, Orfeo T, Mann KG. Rivaroxaban delivery and reversal at a venous flow rate. Arterioscler Thromb Vasc Biol 2012;32(12):2877–83. [6] Stöllberger C, Finsterer J. Stroke and urosepsis after discontinuation of rivaroxaban. Int J Cardiol 2013;169(5):e77–8.
Please cite this article as: Adams CB, et al, Superior mesenteric artery thrombosis after abrupt discontinuation of rivaroxaban, Am J Emerg Med (2015), http://dx.doi.org/10.1016/j.ajem.2015.08.053
