Case Report For reprint orders, please contact: [email protected]
Reversal of rivaroxaban anticoagulation by nonactivated prothrombin complex concentrate in urgent surgery
Carolina Chic Acevedo*,1, Francisco Velasco1 & Concepción Herrera1
Abstract Rivaroxaban is a once daily oral anticoagulant currently indicated for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the prevention and treatment of venous or pulmonary thromboembolism. Despite the known advantages of rivaroxaban over standard therapy, this treatment is not exempt from bleeding. We present the case of a 51-year-old woman with arterial hypertension and paroxysmal atrial fibrillation anticoagulated with rivaroxaban 20 mg o.d. Patient was admitted to the emergency department because of intense abdominal pain, high temperature, hypotension, tachycardia and a big tumor in the right abdominal area. The ultrasonic exam showed a big collection in the thoracic and abdominal area, compatible with hematoma. Due to clinical instability, urgent surgery was required. Based on the results of coagulation parameters (PT: 17.5 s), the time from the last rivaroxaban dose was taken, and the patient weight, nonactivated prothrombin complex concentrate at a single dose of 1000 IU was administrated intravenously 1 h before the surgery. PT value decreased to normal value (13.5 s), and surgery was performed without any bleeding complication. The management of patients treated with rivaroxaban who require urgent surgery is discussed in this report. Direct new oral anticoagulants have improved the management of patients with nonvalvular atrial fibrillation (NVAF), deep vein thrombosis or pulmonary embolism [1–5] . Thus, in patients with NVAF, rivaroxaban is at least as effective as warfarin for the prevention of stroke and systemic embolism, but with a 33% and a 50% lower risk of intracranial hemorrhage and fatal bleeding, respectively [5] . In addition, rivaroxaban has a predictable anticoagulant effect, a wide therapeutic window and a rapid onset and ending of action. Moreover, no interactions with food have been described and only a few interactions with other drugs have been reported. As a result, no monitoring of its anticoagulant effect is required and fixed doses can be prescribed [6] . Despite these advantages over standard therapy, rivaroxaban is not exempt from bleeding. Since rivaroxaban has recently been marketed, some doubts about the best approach may emerge when bleeding occurs or when urgent surgery is required. In this clinical case, the management of a patient treated with rivaroxaban that requires urgent surgery is reported.
Keywords
• atrial fibrillation • bleeding • hematoma • nonactivated
prothrombin complex concentrate • rivaroxaban • surgery
Clinical case ●●Presentation of case
A 51-year-old woman with arterial hypertension, chronic venous insufficiency, paroxysmal AF and normal renal function (creatinine clearance 100 ml/min), was being treated with enalapril 20 mg b.i.d. and rivaroxaban 20 mg o.d. 1 Hematology Service, Hospital Universitario Reina Sofía, Córdoba, Spain *Author for correspondence: Tel.: + 34 615401111; [email protected]
10.2217/FCA.15.38 © 2015 Future Medicine Ltd
Future Cardiol. (Epub ahead of print)
part of
ISSN 1479-6678-0794
Case Report Chic Acevedo, Velasco & Herrera
Figure 1. Abdominal echography. 9.8 × 5.3 cm diameter intramuscular anechoic and well delimited collection with echogenic material inside.
After a physical effort, patient had a sudden abdominal pain and 2 days later, a mass appeared in the right abdominal area. After 1 week, she was admitted to the emergency department due to intense abdominal pain, hypotension (80/40 mmHg), tachycardia (140 bpm), high temperature (40°C), decreased urine output and a big tumor in the right abdominal area. ●●Initial diagnosis/assessment
An urgent abdominal ultrasonic exam was performed. It showed a 9.8 × 5.3 cm diameter intramuscular anechoic and well-delimited collection with echogenic material inside compatible with encapsulated hematoma (Figure 1) . Blood analysis showed: hemoglobin 10 g/l, mean corpuscular volume 80 fl, platelets 400 × 109/l and serum creatinine 0.09 g/l (creatinine clearance 82 ml/min). The rest of parameters were within normal range. Intravenous antibiotic and fluid therapy was started. Taking into account the clinical and
Figure 2. Computerized axial tomography scan. 7 cm diameter collection next to the abdominal oblique muscle with homogeneous peripheral enhancement.
10.2217/FCA.15.38
Future Cardiol. (Epub ahead of print)
ultrasonic data, an urgent computerized axial tomography scan was performed to complete the diagnostic approach. A 7 cm diameter collection next to the abdominal oblique muscle was observed. The lesion showed a homogeneous peripheral enhancement. These observations were compatible with an encapsulated hematoma (Figure 2) . Due to clinical instability of the patient, urgent surgery was considered. The last dose of rivaroxaban had been taken 8 h before. The coagulation parameters obtained in the emergency department were: prothrombin time (PT): 17.5 s (8.5–13.6 s); INR: 1.40 (0.8–1.2); prothrombin activity: 47% (80–120%); activated partial thromboplastin time (aPTT): 42.2 s (21–40 s); aPTT ratio: 1.24 (0.80–1.30). ●●Evolution
Based on the results of coagulation parameters, the time from the last rivaroxaban dose was taken, and the patient weight, nonactivated prothrombin complex concentrate (PCC) (Octaplex®) at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously 1 h before the surgery. After PCC administration, coagulation parameters were: PT: 13.5 s; INR: 1.1; prothrombin activity: 75.5%; aPTT: 38.9 s; aPTT ratio: 1.14 (Table 1) . After PT normalization, surgery was performed. A big abscess cavity was observed during the intervention and the lesion was drained. No complications were reported during surgery and no more hemostatic support was needed. The patient remained clinically stable and high temperature normalized 48 h after surgery. Blood analysis after surgery showed: hemoglobin 9.0 g/l, platelets 360 × 109/l and serum creatinine 0.07 g/l. Twenty four hours after the surgery, rivaroxaban was restarted. No further hemorrhagic complications were reported. Discussion & conclusion Some relevant issues should be discussed after reading this clinical case: the need of anticoagulation, the best approach when bleeding occurs in a patient taking rivaroxaban, the most useful coagulation parameters to be determined in this context and how rivaroxaban anticoagulant activity should be reversed. Regarding the need of anticoagulation, this was a 51-year-old woman with a history of hypertension and paroxysmal AF. CHA 2DS2-VASc score was 2 (arterial hypertension and female sex). As
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Reversal of rivaroxaban anticoagulation by prothrombin complex concentrate
Case Report
Table 1. Coagulation parameters determined in the emergency department, before and after the administration of nonactivated prothrombin complex concentrate. Parameter
At admission
After the administration of PCC
Reference range
Prothrombin activity (%) INR PT (s) aPTT (s) aPTT ratio
47 1.40 17.5 42.2 1.24
75.5 1.10 13.5 38.9 1.14
80–120 0.8–1.2 8.5–13.6 21.0–40.0 0.80–1.30
aPTT: Activated partial thromboplastin time; INR: International normalized ratio; PCC: Nonactivated prothrombin complex concentrate; PT: Prothrombin time.
a result, the annual risk of stroke was 2.2% [7–9] . Therefore, anticoagulation was indeed indicated. When a clinically significant bleeding occurs, establishing the hemorrhage severity and location as well as ensuring adequate hemodynamic stability is mandatory [10] . Rivaroxaban, a direct Xa inhibitor, is a new oral anticoagulant. The maximum plasma concentration of rivaroxaban is achieved only 3 h after ingestion. Half-life of rivaroxaban is 5–9 h in young individuals, and 11–13 h in elderly subjects [11] . It has been estimated that hemostasis is completely restored after 16–24 h of the last dose taken in patients without renal insufficiency. As a result, when urgent surgery is required, delaying the moment of surgery is preferable when possible [10,11] . When surgery cannot be delayed (i.e., emergency surgery, hemodynamic instability, risk of fatal bleeding), it is necessary to reverse the anticoagulant activity of rivaroxaban. Although a specific antidote for this drug is not currently available, Phase II studies have demonstrated that andexanet alpha effectively reverses the anticoagulant activity of rivaroxaban [12] . On the other hand, several in vitro studies as well as preclinical studies have shown that PCC has the potential to reverse the anticoagulant activity of rivaroxaban [13–17] . In addition, these data have been confirmed in studies performed in healthy volunteers [18,19] . However, to date, no data have been reported about reversal of anticoagulant activity of rivaroxaban with PCC in patients with an active bleeding. Current updates only recommend reversal of rivaroxaban activity in case of active life-threatening bleeding but not in case of surgery. In fact, a number of cases in which the reversal of anticoagulant activity of rivaroxaban was required due to bleeding have been published [20] . However, in our case, PCC was used because the lesion was considered to be life-threatening owing to the clinical instability of the patient. With regard to the PCC dosage, it depends on the time last dose of rivaroxaban was taken (more time, lower dose) [21] .
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Although monitoring the anticoagulant activity of rivaroxaban is not routinely required, in some cases it may be useful (i.e., urgent surgery). Rivaroxaban mainly prolongs PT, but it has not a significant effect on aPTT or thrombin time. The measurement of antifactor Xa activity with chromogenic assays is the most sensitive determination of the anticoagulant activity of rivaroxaban. Unfortunately, this method was not available in our center. Of note, INR determination is not useful in this context [10] . Based on the results of coagulation parameters, the time from the last rivaroxaban dose was taken, and the patient weight, PCC at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously. After PCC administration, PT was reduced to 13 s. If rivaroxaban had recently been taken and maximum concentrations had been reached, almost 3500 IU (50 IU/Kg) had been administered [22] . In conclusion, although delaying the time of surgery in patients treated with rivaroxaban who require surgery may be sufficient to ensure an adequate hemostasis in the majority of cases, in those patients who require urgent surgery or when active bleeding is important, the use of PCC is useful to reverse the anticoagulant activity of rivaroxaban. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Editorial assitance was provided by Content Ed Net, Madrid, Spain, with funding from Bayer.
Informed consent disclosure The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
www.futuremedicine.com
10.2217/FCA.15.38
Case Report Chic Acevedo, Velasco & Herrera Executive summary Background ●●
Rivaroxaban is a once daily direct oral anticoagulant currently indicated for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
●●
Despite the known advantages of rivaroxaban over standard therapy, this treatment is not exempt from bleeding.
●●
The management of patients treated with rivaroxaban who require urgent surgery is discussed in this report.
Clinical case ●●
We present the case of a 51-year-old woman with arterial hypertension and paroxysmal atrial fibrillation treated with rivaroxaban 20 mg o.d.
●●
Patient was admitted to the emergency department because of intense abdominal pain, high temperature,
hypotension, tachycardia and a big tumor in the right abdominal area. The ultrasonic exam showed a big collection in the thoracic and abdominal area. ●●
Urgent surgery was considered. Based on the results of coagulation parameters (PT: 17.5 s), the time from the last
rivaroxaban dose was taken, and the patient weight, prothrombin complex concentrate at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously 1 h before the surgery. PT value decreased to normal value (PT: 13.5 s), and surgery was performed without any bleeding complication. Discussion & conclusion ●●
When surgery is required, delaying surgery until 24 h after the last dose of rivaroxaban is preferred.
●●
When this is not possible (i.e., emergency surgery, hemodynamic instability or risk of fatal bleeding), it is necessary to reverse the anticoagulant activity of rivaroxaban.
●●
Although a specific antidote for rivaroxaban is not currently available, it has been demonstrated that prothrombin complex concentrate rapidly reverses the anticoagulant effect of rivaroxaban in healthy volunteers.
References
5
Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
•
2
3
4
Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N. Engl. J. Med. 358(26), 2765–2775 (2008). In RECORD1, a once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N. Engl. J. Med. 358(26), 2776–2786 (2008). EINSTEIN Investigators, Bauersachs R, Berkowitz SD et al. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363(26), 2499–2510 (2010). EINSTEIN–PE Investigators, Büller HR, Prins MH et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N. Engl. J. Med. 366(14), 1287–1297 (2012).
10.2217/FCA.15.38
Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365(10), 883–891 (2011).
•• In ROCKET-AF, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (NVAF), with a lesser risk of intracranial and fatal bleeding. 6
Barrios V, Escobar C. Rivaroxaban: a once-daily anticoagulant for the prevention of thromboembolic complications. Expert Rev. Cardiovasc. Ther. 11(2), 129–141 (2013).
7
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest 137(2), 263–272 (2010).
8
Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest 138(5), 1093–100 (2010).
Future Cardiol. (Epub ahead of print)
9
Camm AJ, Lip GY, De Caterina R et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation * Developed with the special contribution of the European Heart Rhythm Association. Eur. Heart. J. 33(21), 2719–2747 (2012).
10 Sánchez M, Escolar G, Reverter JC. Bleeding in
patients on anticoagulant therapy: the real utility of antidotes and how to manage bleeding in patients on new-generation oral anticoagulants. Emergencias 25, 482–490 (2013). 11 European Medicines Agency (EMA). Xarelto®,
“Summary of Product Characteristics”. Last update 15-August-2013. www.ema.europa.eu 12 Mark C, Vandana M, Michael K et al. A Phase
2 Randomized, Double-Blind, PlaceboControlled Trial Demonstrating Reversal Of Rivaroxaban-Induced Anticoagulation In Healthy Subjects By Andexanet Alfa (PRT064445), An Antidote For Fxa Inhibitors. Presented at: 55th American Society of Hematology (ASH) Annual Meeting and Exposition. New Orleans, LA, 7–10 December 2013 (Abstract A3636).
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Reversal of rivaroxaban anticoagulation by prothrombin complex concentrate 13 Perzborn E, Heitmeier S, Laux V, Buchmüller
A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb. Res. 133(4), 671–681 (2014).
17 Godier A, Miclot A, Le Bonniec B et al.
Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 116(1), 94–102 (2012). 18 Marlu R, Hodaj E, Paris A et al. Effect of
non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb. Haemost. 108(2), 217–224 (2012).
14 Dinkelaar J, Molenaar PJ, Ninivaggi M et al.
In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for Rivaroxaban. J. Thromb. Haemost. 11(6), 1111–1118 (2013).
19 Eerenberg ES, Kamphuisen PW, Sijpkens
MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124(14), 1573–1579 (2011).
15 Herzog E, Kaspereit F, Krege W et al.
Correlation of coagulation markers and 4F-PCC-mediated reversal of rivaroxaban in a rabbit model of acute bleeding. Thromb. Res. 135(3), 554–560 (2015). 16 Perzborn E, Gruber A, Tinel H et al. Reversal
of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb. Haemost. 110(1), 162–172 (2013).
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•
In this study, prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of
Case Report
rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran. 20 Nannapaneni N, Singh R, Mckay P,
Al-Hajeili M. Managing a rivaroxaban bleed: understanding the difficulties in acute reversal of the new oral anticoagulants through a case report. Case Rep. Hematol. 2014, 548272 (2014). 21 Dickneite G, Hoffman M. Reversing the new
oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb. Haemost. 111(2), 189–198 (2014). 22 Escolar G, Arellano-Rodrigo E, Lopez-
Vilchez I et al. Reversal of rivaroxabaninduced alterations on hemostasis by different coagulation factor concentrates. Circ. J. 79(2), 331–338 (2015).
www.futuremedicine.com
10.2217/FCA.15.38
Reversal of rivaroxaban anticoagulation by nonactivated prothrombin complex concentrate in urgent surgery
Carolina Chic Acevedo*,1, Francisco Velasco1 & Concepción Herrera1
Abstract Rivaroxaban is a once daily oral anticoagulant currently indicated for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the prevention and treatment of venous or pulmonary thromboembolism. Despite the known advantages of rivaroxaban over standard therapy, this treatment is not exempt from bleeding. We present the case of a 51-year-old woman with arterial hypertension and paroxysmal atrial fibrillation anticoagulated with rivaroxaban 20 mg o.d. Patient was admitted to the emergency department because of intense abdominal pain, high temperature, hypotension, tachycardia and a big tumor in the right abdominal area. The ultrasonic exam showed a big collection in the thoracic and abdominal area, compatible with hematoma. Due to clinical instability, urgent surgery was required. Based on the results of coagulation parameters (PT: 17.5 s), the time from the last rivaroxaban dose was taken, and the patient weight, nonactivated prothrombin complex concentrate at a single dose of 1000 IU was administrated intravenously 1 h before the surgery. PT value decreased to normal value (13.5 s), and surgery was performed without any bleeding complication. The management of patients treated with rivaroxaban who require urgent surgery is discussed in this report. Direct new oral anticoagulants have improved the management of patients with nonvalvular atrial fibrillation (NVAF), deep vein thrombosis or pulmonary embolism [1–5] . Thus, in patients with NVAF, rivaroxaban is at least as effective as warfarin for the prevention of stroke and systemic embolism, but with a 33% and a 50% lower risk of intracranial hemorrhage and fatal bleeding, respectively [5] . In addition, rivaroxaban has a predictable anticoagulant effect, a wide therapeutic window and a rapid onset and ending of action. Moreover, no interactions with food have been described and only a few interactions with other drugs have been reported. As a result, no monitoring of its anticoagulant effect is required and fixed doses can be prescribed [6] . Despite these advantages over standard therapy, rivaroxaban is not exempt from bleeding. Since rivaroxaban has recently been marketed, some doubts about the best approach may emerge when bleeding occurs or when urgent surgery is required. In this clinical case, the management of a patient treated with rivaroxaban that requires urgent surgery is reported.
Keywords
• atrial fibrillation • bleeding • hematoma • nonactivated
prothrombin complex concentrate • rivaroxaban • surgery
Clinical case ●●Presentation of case
A 51-year-old woman with arterial hypertension, chronic venous insufficiency, paroxysmal AF and normal renal function (creatinine clearance 100 ml/min), was being treated with enalapril 20 mg b.i.d. and rivaroxaban 20 mg o.d. 1 Hematology Service, Hospital Universitario Reina Sofía, Córdoba, Spain *Author for correspondence: Tel.: + 34 615401111; [email protected]
10.2217/FCA.15.38 © 2015 Future Medicine Ltd
Future Cardiol. (Epub ahead of print)
part of
ISSN 1479-6678-0794
Case Report Chic Acevedo, Velasco & Herrera
Figure 1. Abdominal echography. 9.8 × 5.3 cm diameter intramuscular anechoic and well delimited collection with echogenic material inside.
After a physical effort, patient had a sudden abdominal pain and 2 days later, a mass appeared in the right abdominal area. After 1 week, she was admitted to the emergency department due to intense abdominal pain, hypotension (80/40 mmHg), tachycardia (140 bpm), high temperature (40°C), decreased urine output and a big tumor in the right abdominal area. ●●Initial diagnosis/assessment
An urgent abdominal ultrasonic exam was performed. It showed a 9.8 × 5.3 cm diameter intramuscular anechoic and well-delimited collection with echogenic material inside compatible with encapsulated hematoma (Figure 1) . Blood analysis showed: hemoglobin 10 g/l, mean corpuscular volume 80 fl, platelets 400 × 109/l and serum creatinine 0.09 g/l (creatinine clearance 82 ml/min). The rest of parameters were within normal range. Intravenous antibiotic and fluid therapy was started. Taking into account the clinical and
Figure 2. Computerized axial tomography scan. 7 cm diameter collection next to the abdominal oblique muscle with homogeneous peripheral enhancement.
10.2217/FCA.15.38
Future Cardiol. (Epub ahead of print)
ultrasonic data, an urgent computerized axial tomography scan was performed to complete the diagnostic approach. A 7 cm diameter collection next to the abdominal oblique muscle was observed. The lesion showed a homogeneous peripheral enhancement. These observations were compatible with an encapsulated hematoma (Figure 2) . Due to clinical instability of the patient, urgent surgery was considered. The last dose of rivaroxaban had been taken 8 h before. The coagulation parameters obtained in the emergency department were: prothrombin time (PT): 17.5 s (8.5–13.6 s); INR: 1.40 (0.8–1.2); prothrombin activity: 47% (80–120%); activated partial thromboplastin time (aPTT): 42.2 s (21–40 s); aPTT ratio: 1.24 (0.80–1.30). ●●Evolution
Based on the results of coagulation parameters, the time from the last rivaroxaban dose was taken, and the patient weight, nonactivated prothrombin complex concentrate (PCC) (Octaplex®) at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously 1 h before the surgery. After PCC administration, coagulation parameters were: PT: 13.5 s; INR: 1.1; prothrombin activity: 75.5%; aPTT: 38.9 s; aPTT ratio: 1.14 (Table 1) . After PT normalization, surgery was performed. A big abscess cavity was observed during the intervention and the lesion was drained. No complications were reported during surgery and no more hemostatic support was needed. The patient remained clinically stable and high temperature normalized 48 h after surgery. Blood analysis after surgery showed: hemoglobin 9.0 g/l, platelets 360 × 109/l and serum creatinine 0.07 g/l. Twenty four hours after the surgery, rivaroxaban was restarted. No further hemorrhagic complications were reported. Discussion & conclusion Some relevant issues should be discussed after reading this clinical case: the need of anticoagulation, the best approach when bleeding occurs in a patient taking rivaroxaban, the most useful coagulation parameters to be determined in this context and how rivaroxaban anticoagulant activity should be reversed. Regarding the need of anticoagulation, this was a 51-year-old woman with a history of hypertension and paroxysmal AF. CHA 2DS2-VASc score was 2 (arterial hypertension and female sex). As
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Reversal of rivaroxaban anticoagulation by prothrombin complex concentrate
Case Report
Table 1. Coagulation parameters determined in the emergency department, before and after the administration of nonactivated prothrombin complex concentrate. Parameter
At admission
After the administration of PCC
Reference range
Prothrombin activity (%) INR PT (s) aPTT (s) aPTT ratio
47 1.40 17.5 42.2 1.24
75.5 1.10 13.5 38.9 1.14
80–120 0.8–1.2 8.5–13.6 21.0–40.0 0.80–1.30
aPTT: Activated partial thromboplastin time; INR: International normalized ratio; PCC: Nonactivated prothrombin complex concentrate; PT: Prothrombin time.
a result, the annual risk of stroke was 2.2% [7–9] . Therefore, anticoagulation was indeed indicated. When a clinically significant bleeding occurs, establishing the hemorrhage severity and location as well as ensuring adequate hemodynamic stability is mandatory [10] . Rivaroxaban, a direct Xa inhibitor, is a new oral anticoagulant. The maximum plasma concentration of rivaroxaban is achieved only 3 h after ingestion. Half-life of rivaroxaban is 5–9 h in young individuals, and 11–13 h in elderly subjects [11] . It has been estimated that hemostasis is completely restored after 16–24 h of the last dose taken in patients without renal insufficiency. As a result, when urgent surgery is required, delaying the moment of surgery is preferable when possible [10,11] . When surgery cannot be delayed (i.e., emergency surgery, hemodynamic instability, risk of fatal bleeding), it is necessary to reverse the anticoagulant activity of rivaroxaban. Although a specific antidote for this drug is not currently available, Phase II studies have demonstrated that andexanet alpha effectively reverses the anticoagulant activity of rivaroxaban [12] . On the other hand, several in vitro studies as well as preclinical studies have shown that PCC has the potential to reverse the anticoagulant activity of rivaroxaban [13–17] . In addition, these data have been confirmed in studies performed in healthy volunteers [18,19] . However, to date, no data have been reported about reversal of anticoagulant activity of rivaroxaban with PCC in patients with an active bleeding. Current updates only recommend reversal of rivaroxaban activity in case of active life-threatening bleeding but not in case of surgery. In fact, a number of cases in which the reversal of anticoagulant activity of rivaroxaban was required due to bleeding have been published [20] . However, in our case, PCC was used because the lesion was considered to be life-threatening owing to the clinical instability of the patient. With regard to the PCC dosage, it depends on the time last dose of rivaroxaban was taken (more time, lower dose) [21] .
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Although monitoring the anticoagulant activity of rivaroxaban is not routinely required, in some cases it may be useful (i.e., urgent surgery). Rivaroxaban mainly prolongs PT, but it has not a significant effect on aPTT or thrombin time. The measurement of antifactor Xa activity with chromogenic assays is the most sensitive determination of the anticoagulant activity of rivaroxaban. Unfortunately, this method was not available in our center. Of note, INR determination is not useful in this context [10] . Based on the results of coagulation parameters, the time from the last rivaroxaban dose was taken, and the patient weight, PCC at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously. After PCC administration, PT was reduced to 13 s. If rivaroxaban had recently been taken and maximum concentrations had been reached, almost 3500 IU (50 IU/Kg) had been administered [22] . In conclusion, although delaying the time of surgery in patients treated with rivaroxaban who require surgery may be sufficient to ensure an adequate hemostasis in the majority of cases, in those patients who require urgent surgery or when active bleeding is important, the use of PCC is useful to reverse the anticoagulant activity of rivaroxaban. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Editorial assitance was provided by Content Ed Net, Madrid, Spain, with funding from Bayer.
Informed consent disclosure The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.
www.futuremedicine.com
10.2217/FCA.15.38
Case Report Chic Acevedo, Velasco & Herrera Executive summary Background ●●
Rivaroxaban is a once daily direct oral anticoagulant currently indicated for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
●●
Despite the known advantages of rivaroxaban over standard therapy, this treatment is not exempt from bleeding.
●●
The management of patients treated with rivaroxaban who require urgent surgery is discussed in this report.
Clinical case ●●
We present the case of a 51-year-old woman with arterial hypertension and paroxysmal atrial fibrillation treated with rivaroxaban 20 mg o.d.
●●
Patient was admitted to the emergency department because of intense abdominal pain, high temperature,
hypotension, tachycardia and a big tumor in the right abdominal area. The ultrasonic exam showed a big collection in the thoracic and abdominal area. ●●
Urgent surgery was considered. Based on the results of coagulation parameters (PT: 17.5 s), the time from the last
rivaroxaban dose was taken, and the patient weight, prothrombin complex concentrate at a single dose of 1000 IU (15 IU/Kg) was administrated intravenously 1 h before the surgery. PT value decreased to normal value (PT: 13.5 s), and surgery was performed without any bleeding complication. Discussion & conclusion ●●
When surgery is required, delaying surgery until 24 h after the last dose of rivaroxaban is preferred.
●●
When this is not possible (i.e., emergency surgery, hemodynamic instability or risk of fatal bleeding), it is necessary to reverse the anticoagulant activity of rivaroxaban.
●●
Although a specific antidote for rivaroxaban is not currently available, it has been demonstrated that prothrombin complex concentrate rapidly reverses the anticoagulant effect of rivaroxaban in healthy volunteers.
References
5
Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
•
2
3
4
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•• In ROCKET-AF, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (NVAF), with a lesser risk of intracranial and fatal bleeding. 6
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patients on anticoagulant therapy: the real utility of antidotes and how to manage bleeding in patients on new-generation oral anticoagulants. Emergencias 25, 482–490 (2013). 11 European Medicines Agency (EMA). Xarelto®,
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In this study, prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of
Case Report
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