International Journal of Cardiology 174 (2014) e75–e76
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Life-threatening haemorrhagic pericarditis associated with rivaroxaban Bo Xu ⁎,1, Andrew MacIsaac Department of Cardiology, St. Vincent's Hospital Melbourne, Victoria Parade, Fitzroy, VIC 3065, Australia
a r t i c l e
i n f o
Article history: Received 9 April 2014 Accepted 12 April 2014 Available online 21 April 2014 Keywords: Cardiac tamponade Rivaroxaban Pericarditis Anticoagulation
A 75-year-old male presented to a regional hospital with central chest pain. His other history included atrial fibrillation and a dualchamber permanent pacemaker inserted for tachy–brady syndrome. His medications included rivaroxaban (20 mg oral daily) and metoprolol (50 mg oral twice daily). The electrocardiogram (ECG) on presentation demonstrated widespread ST-segment elevation, most prominently in leads I, II, V5 and V6. It was initially suspected that the patient suffered from a ST-segment elevation myocardial infarct. However, in view of his anticoagulation with rivaroxaban, he did not receive thrombolysis. The patient was commenced on anti-platelet therapy, including loading doses of aspirin (300 mg) and ticagrelor (180 mg), and subsequent maintenance doses of aspirin (100 mg oral daily) and ticagrelor (90 mg oral twice daily). Serial cardiac enzymes were subsequently found to be negative. The clinical diagnosis was changed to pericarditis. His ticagrelor was ceased but aspirin and rivaroxaban were continued on day 1. Additionally, regular ibuprofen (400 mg oral three times daily), paracetamol (1 g oral four times daily) and colchicine (0.5 mg oral daily) were added to treat pericardial pain. The patient also received two additional doses of ibuprofen (400 mg) on an as-needed basis. On day 2 of admission, the patient deteriorated significantly. He became shocked with a systolic blood pressure of 80 mm Hg. ECG demonstrated atrial fibrillation with a rapid ventricular response rate, with significant widespread ST-segment elevation (Fig. 1). Chest X-ray
⁎ Corresponding author at: Department of Cardiology, St. Vincent's Hospital Melbourne, Victoria Parade, Fitzroy, VIC 3065, Australia. Tel.: +61 3 9288 2211; fax: +61 3 9288 4422. E-mail addresses: [email protected] (B. Xu), [email protected] (A. MacIsaac). 1 Tel.: +61 3 9288 2211; fax: +61 3 9288 4422.
http://dx.doi.org/10.1016/j.ijcard.2014.04.151 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
demonstrated normal mediastinal contour, with appropriate positioning of the pacemaker leads. A bedside transthoracic echocardiogram confirmed a moderate sized pericardial effusion. A pericardial drain was inserted which initially drained 250 mL of heavily blood stained fluid. There was an immediate and dramatic improvement in the patient's clinical state following the pericardiocentesis. The patient was transferred to our centre for further management. Transthoracic echocardiogram performed on arrival demonstrated normal bi-ventricular size and systolic function. There was minimal residual pericardial effusion. A computed tomography (CT) aortogram study excluded acute aortic dissection. The patient's serum creatinine, which was normal on presentation to the regional centre, became elevated at 150 μmol/L (normal range: 64–104 μmol/L). He also developed an acute elevation of his liver enzymes predominantly alanine transaminase (ALT; peak at 2310 units/L; normal range: b45 units/L). This was attributed to acute ischaemic hepatitis, which improved over 10 days. Most importantly, the patient developed a coagulopathy with an elevated international normalised ratio (INR; 4.5; normal range: 0.8–1.2) and an elevated activated plasma thromboplastin time (APTT; 55; normal range: 26–40) on the day of arrival at our centre. Thrombin clotting time (TCT) performed the next day was within normal range at 16 seconds (normal: b 21 seconds). Anti-factor Xa activity was 25 ng/mL. He received 2 units of fresh frozen plasma and general supportive care. The patient's dual chamber pacemaker was pacing and sensing appropriately on interrogation. On further questioning, rivaroxaban was commenced at 20 mg oral daily by his usual cardiologist for atrial fibrillation 4 months prior to presentation. His dual chamber permanent pacemaker was inserted 3 months prior to presentation for tachy–brady syndrome. Interestingly, rivaroxaban was only withheld on the day of pacemaker insertion, with recommencement of rivaroxaban day 1 following pacemaker insertion. The pericardial catheter continued to drain small amounts of blood over the next few days. On day 4, the pigtail catheter was removed, having drained a total of 1000 mL of heavily blood stained fluid since insertion. The presence of blood in the pericardial drain was confirmed by cytological examination. The patient's coagulopathy gradually improved with supportive care. Repeat transthoracic echocardiogram confirmed no further re-accumulation of pericardial effusion. The patient's rivaroxaban had been stopped on day 2 of presentation to the regional centre. He was discharged home on day 10 of admission at our centre. To date, he has remained clinically well. Anticoagulation, especially with heparin, has been previously documented to produce haemorrhagic cardiac tamponade in the presence of pericarditis [1,2]. However this report demonstrates that haemorrhagic cardiac tamponade can also occur with the novel anticoagulant rivaroxaban. This is especially the case when anti-platelet and non-
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B. Xu, A. MacIsaac / International Journal of Cardiology 174 (2014) e75–e76
Fig. 1. ECG demonstrated widespread ST-segment elevation. At the time the ECG was taken, the patient was in shock with a blood pressure of 80/60 mm Hg.
steroidal anti-inflammatory drugs are also used, in the presence of transient renal impairment. This case initially presented a diagnostic dilemma. At the time of presentation, the diagnosis of acute STsegment elevation myocardial infarction was considered, however the clinical presentation, ECG changes and normal troponin subsequently established a diagnosis of pericarditis. When the patient acutely deteriorated, several alternative diagnoses were possible. Acute aortic dissection was excluded by a CT aortogram study. Ventricular perforation due to pacing leads was less likely, given that the pacemaker was inserted 3 months prior to presentation. Additionally, the pacing leads were in stable, appropriate positions on chest X-ray, with appropriate sensing and pacing on interrogation. To the best of our knowledge, this is the first report of life threatening haemorrhagic pericarditis causing cardiac tamponade associated with rivaroxaban. Rivaroxaban is a novel factor Xa inhibitor [3,4]. It has a plasma half-life of 7 to 11 hours, with one-third being renally eliminated as the active drug unchanged and another third being renally eliminated as inactive metabolites [5]. In this case, transient renal impairment, whether due to the effects of non-steroidal anti-inflammatory medications or decreased renal perfusion as a result of cardiac tamponade, may have decreased renal clearance of rivaroxaban. Currently, no single routinely available laboratory test specifically measures the anti-coagulant effect of rivaroxaban. In the events of serious bleeding, no specific antidotes or reversal agents are available [6]. Several non-specific haemostatic agents, including activated prothrombin complex concentrate and recombinant factor VIIa, have been studied [7–9]. Currently, there are no consensus guidelines on the management of patients on novel anticoagulants such as rivaroxaban. Specifically, there are no guidelines on the management of bleeding events while on novel anticoagulants. This case highlights the urgent need for consensus guidelines on the management of patients on novel anticoagulants, including rivaroxaban. Specific guidelines are also needed to address the increasingly common clinical scenarios with regard to the combination of these drugs with antiplatelet agents, and drugs that are likely to impair renal function, and
the management of patients on novel anticoagulants requiring emergency or elective surgery or invasive procedures. One important clinical lesson from this case is that cardiac tamponade should be considered, when there is widespread ST-segment elevation on ECG and shock. Another important clinical lesson from this case is that medications should be used judiciously for patients on an anticoagulant, whether it is warfarin or one of the novel anticoagulants. The use of anti-platelet medications, non-steroidal anti-inflammatory medications and other medications that could increase the risk of bleeding, should be carefully reviewed for any patient on an anticoagulant. The “triple whammy” of anti-platelet agents, non-steroidal anti-inflammatory agents and anticoagulants should be avoided. References [1] Belic L, Stafford G, Allen JW, Venkataraman K. Cardiac tamponade during anticoagulation management with a pericardial drain and continued anticoagulation. JAMA 1978;240(7):672. [2] Goodman HL. Acute nonspecific pericarditis with cardiac tamponade: a fatal case associated with anticoagulation therapy. Ann Intern Med 1958;48(2):406–15. [3] Patel MR, Mahaffey KW, Garf J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [4] Xu B, Whitbourn R. Novel anticoagulants for non-valvular atrial fibrillation. Heart Lung Circ 2012;21(8):463–7. [5] Weitz JI, Eikelboom JW, Samama MM. New antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl. 2):e120S–51S. [6] Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med 2013;80(7):443–51. [7] Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. [8] 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 2011;124:1573–9. [9] 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 2012;116(1):94–102.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Life-threatening haemorrhagic pericarditis associated with rivaroxaban Bo Xu ⁎,1, Andrew MacIsaac Department of Cardiology, St. Vincent's Hospital Melbourne, Victoria Parade, Fitzroy, VIC 3065, Australia
a r t i c l e
i n f o
Article history: Received 9 April 2014 Accepted 12 April 2014 Available online 21 April 2014 Keywords: Cardiac tamponade Rivaroxaban Pericarditis Anticoagulation
A 75-year-old male presented to a regional hospital with central chest pain. His other history included atrial fibrillation and a dualchamber permanent pacemaker inserted for tachy–brady syndrome. His medications included rivaroxaban (20 mg oral daily) and metoprolol (50 mg oral twice daily). The electrocardiogram (ECG) on presentation demonstrated widespread ST-segment elevation, most prominently in leads I, II, V5 and V6. It was initially suspected that the patient suffered from a ST-segment elevation myocardial infarct. However, in view of his anticoagulation with rivaroxaban, he did not receive thrombolysis. The patient was commenced on anti-platelet therapy, including loading doses of aspirin (300 mg) and ticagrelor (180 mg), and subsequent maintenance doses of aspirin (100 mg oral daily) and ticagrelor (90 mg oral twice daily). Serial cardiac enzymes were subsequently found to be negative. The clinical diagnosis was changed to pericarditis. His ticagrelor was ceased but aspirin and rivaroxaban were continued on day 1. Additionally, regular ibuprofen (400 mg oral three times daily), paracetamol (1 g oral four times daily) and colchicine (0.5 mg oral daily) were added to treat pericardial pain. The patient also received two additional doses of ibuprofen (400 mg) on an as-needed basis. On day 2 of admission, the patient deteriorated significantly. He became shocked with a systolic blood pressure of 80 mm Hg. ECG demonstrated atrial fibrillation with a rapid ventricular response rate, with significant widespread ST-segment elevation (Fig. 1). Chest X-ray
⁎ Corresponding author at: Department of Cardiology, St. Vincent's Hospital Melbourne, Victoria Parade, Fitzroy, VIC 3065, Australia. Tel.: +61 3 9288 2211; fax: +61 3 9288 4422. E-mail addresses: [email protected] (B. Xu), [email protected] (A. MacIsaac). 1 Tel.: +61 3 9288 2211; fax: +61 3 9288 4422.
http://dx.doi.org/10.1016/j.ijcard.2014.04.151 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
demonstrated normal mediastinal contour, with appropriate positioning of the pacemaker leads. A bedside transthoracic echocardiogram confirmed a moderate sized pericardial effusion. A pericardial drain was inserted which initially drained 250 mL of heavily blood stained fluid. There was an immediate and dramatic improvement in the patient's clinical state following the pericardiocentesis. The patient was transferred to our centre for further management. Transthoracic echocardiogram performed on arrival demonstrated normal bi-ventricular size and systolic function. There was minimal residual pericardial effusion. A computed tomography (CT) aortogram study excluded acute aortic dissection. The patient's serum creatinine, which was normal on presentation to the regional centre, became elevated at 150 μmol/L (normal range: 64–104 μmol/L). He also developed an acute elevation of his liver enzymes predominantly alanine transaminase (ALT; peak at 2310 units/L; normal range: b45 units/L). This was attributed to acute ischaemic hepatitis, which improved over 10 days. Most importantly, the patient developed a coagulopathy with an elevated international normalised ratio (INR; 4.5; normal range: 0.8–1.2) and an elevated activated plasma thromboplastin time (APTT; 55; normal range: 26–40) on the day of arrival at our centre. Thrombin clotting time (TCT) performed the next day was within normal range at 16 seconds (normal: b 21 seconds). Anti-factor Xa activity was 25 ng/mL. He received 2 units of fresh frozen plasma and general supportive care. The patient's dual chamber pacemaker was pacing and sensing appropriately on interrogation. On further questioning, rivaroxaban was commenced at 20 mg oral daily by his usual cardiologist for atrial fibrillation 4 months prior to presentation. His dual chamber permanent pacemaker was inserted 3 months prior to presentation for tachy–brady syndrome. Interestingly, rivaroxaban was only withheld on the day of pacemaker insertion, with recommencement of rivaroxaban day 1 following pacemaker insertion. The pericardial catheter continued to drain small amounts of blood over the next few days. On day 4, the pigtail catheter was removed, having drained a total of 1000 mL of heavily blood stained fluid since insertion. The presence of blood in the pericardial drain was confirmed by cytological examination. The patient's coagulopathy gradually improved with supportive care. Repeat transthoracic echocardiogram confirmed no further re-accumulation of pericardial effusion. The patient's rivaroxaban had been stopped on day 2 of presentation to the regional centre. He was discharged home on day 10 of admission at our centre. To date, he has remained clinically well. Anticoagulation, especially with heparin, has been previously documented to produce haemorrhagic cardiac tamponade in the presence of pericarditis [1,2]. However this report demonstrates that haemorrhagic cardiac tamponade can also occur with the novel anticoagulant rivaroxaban. This is especially the case when anti-platelet and non-
e76
B. Xu, A. MacIsaac / International Journal of Cardiology 174 (2014) e75–e76
Fig. 1. ECG demonstrated widespread ST-segment elevation. At the time the ECG was taken, the patient was in shock with a blood pressure of 80/60 mm Hg.
steroidal anti-inflammatory drugs are also used, in the presence of transient renal impairment. This case initially presented a diagnostic dilemma. At the time of presentation, the diagnosis of acute STsegment elevation myocardial infarction was considered, however the clinical presentation, ECG changes and normal troponin subsequently established a diagnosis of pericarditis. When the patient acutely deteriorated, several alternative diagnoses were possible. Acute aortic dissection was excluded by a CT aortogram study. Ventricular perforation due to pacing leads was less likely, given that the pacemaker was inserted 3 months prior to presentation. Additionally, the pacing leads were in stable, appropriate positions on chest X-ray, with appropriate sensing and pacing on interrogation. To the best of our knowledge, this is the first report of life threatening haemorrhagic pericarditis causing cardiac tamponade associated with rivaroxaban. Rivaroxaban is a novel factor Xa inhibitor [3,4]. It has a plasma half-life of 7 to 11 hours, with one-third being renally eliminated as the active drug unchanged and another third being renally eliminated as inactive metabolites [5]. In this case, transient renal impairment, whether due to the effects of non-steroidal anti-inflammatory medications or decreased renal perfusion as a result of cardiac tamponade, may have decreased renal clearance of rivaroxaban. Currently, no single routinely available laboratory test specifically measures the anti-coagulant effect of rivaroxaban. In the events of serious bleeding, no specific antidotes or reversal agents are available [6]. Several non-specific haemostatic agents, including activated prothrombin complex concentrate and recombinant factor VIIa, have been studied [7–9]. Currently, there are no consensus guidelines on the management of patients on novel anticoagulants such as rivaroxaban. Specifically, there are no guidelines on the management of bleeding events while on novel anticoagulants. This case highlights the urgent need for consensus guidelines on the management of patients on novel anticoagulants, including rivaroxaban. Specific guidelines are also needed to address the increasingly common clinical scenarios with regard to the combination of these drugs with antiplatelet agents, and drugs that are likely to impair renal function, and
the management of patients on novel anticoagulants requiring emergency or elective surgery or invasive procedures. One important clinical lesson from this case is that cardiac tamponade should be considered, when there is widespread ST-segment elevation on ECG and shock. Another important clinical lesson from this case is that medications should be used judiciously for patients on an anticoagulant, whether it is warfarin or one of the novel anticoagulants. The use of anti-platelet medications, non-steroidal anti-inflammatory medications and other medications that could increase the risk of bleeding, should be carefully reviewed for any patient on an anticoagulant. The “triple whammy” of anti-platelet agents, non-steroidal anti-inflammatory agents and anticoagulants should be avoided. References [1] Belic L, Stafford G, Allen JW, Venkataraman K. Cardiac tamponade during anticoagulation management with a pericardial drain and continued anticoagulation. JAMA 1978;240(7):672. [2] Goodman HL. Acute nonspecific pericarditis with cardiac tamponade: a fatal case associated with anticoagulation therapy. Ann Intern Med 1958;48(2):406–15. [3] Patel MR, Mahaffey KW, Garf J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [4] Xu B, Whitbourn R. Novel anticoagulants for non-valvular atrial fibrillation. Heart Lung Circ 2012;21(8):463–7. [5] Weitz JI, Eikelboom JW, Samama MM. New antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl. 2):e120S–51S. [6] Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med 2013;80(7):443–51. [7] Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–24. [8] 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 2011;124:1573–9. [9] 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 2012;116(1):94–102.
