00941
2013
AOPXXX10.1177/1060028013500941Faust et alThe Annals of Pharmacotherapy
Case Report
Acute Ischemic Stroke Following Cardioversion in a Patient Receiving Dabigatran
Annals of Pharmacotherapy 47(10) 1368–1371 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500941 aop.sagepub.com
Andrew C. Faust, PharmD, BCPS1, Megan B. Smith, PharmD, BCPS1,2, and Darryl Kawalsky, MD, FACC, FACP3
Abstract Objective: To report a case of acute ischemic stroke following electrical cardioversion in a patient currently anticoagulated with dabigatran 150 mg twice daily. Case Summary: A 74-year-old man, who had been adherent with more than 6 weeks of dabigatran 150 mg twice daily therapy, presented with a dense left-sided hemiparesis 72 hours following a repeat electrical cardioversion. Both computed tomography and magnetic resonance angiogram confirmed a right middle cerebral artery infarct. A transesophageal echocardiogram performed after the cerebrovascular accident failed to demonstrate a cardiac source of embolus. The patient previously underwent cardioversion 4 weeks prior with no evidence at that time of thrombus or spontaneous echo contrast on transesophageal echocardiogram. Discussion: Dabigatran was approved in the United States in late 2010 for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Post hoc data from the phase III trial suggest a low risk of embolism following cardioversion. Since there are no conventional coagulation measures to reliably demonstrate the level of anticoagulation in patients on dabigatran, clinicians must rely solely on patient history when assessing the safety of cardioverting a patient on this medication. Data have suggested increased pro-inflammatory mediators and increased risk of myocardial infarction with oral direct thrombin inhibitors, which may have manifested as a cerebral or carotid artery thrombosis in situ. Conclusion: Novel oral anticoagulants are attractive options for anticoagulation required with cardioversion. Although this case report may not preclude use of dabigatran for this purpose, it illustrates that use of this drug is not without risks. Additional investigation into the proinflammatory nature of the oral direct thrombin inhibitors is needed. Keywords dabigatran, cardioversion, ischemic stroke
Background
Case Report
Dabigatran etexilate (dabigatran) was approved by the US Food and Drug Administration in late 2010 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 This approval was based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which found dabigatran 150 mg twice daily to be superior to warfarin with regard to stroke or systemic embolism (relative risk = 0.66; 95% confidence interval = 0.53-0.82; P < .001).2 Post hoc data analysis from RE-LY suggests a low risk of stroke and systemic embolism at 30 days following cardioversion with use of dabigatran 150 mg twice daily.3 Despite the use of transesophageal echocardiography (TEE) and more than 6 weeks of anticoagulation with dabigatran 150 mg twice daily, we describe a patient who suffered an ischemic stroke approximately 72 hours following cardioversion.
The patient is a 74-year-old, 71-kg man with a known history of nonvalvular atrial fibrillation on chronic anticoagulation, coronary artery disease, hypertensive heart disease, and sleep apnea on a home continuous positive airway pressure machine. He presented as an outpatient with recurrent symptomatic atrial fibrillation. Several weeks prior to this outpatient visit, he was converted from warfarin to 1
Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA Texas Tech University Health Science Center, Dallas, TX, USA 3 North Texas Heart Center, Dallas, TX, USA 2
Corresponding Author: Andrew C. Faust, PharmD, BCPS, Department of Pharmacy, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231, USA. Email: [email protected]
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Faust et al dabigatran 150 mg twice daily at his request. The patient’s CHADS2 score was calculated as 1 and his CHA2DS2-VASc score was 3. Electrical cardioversion was recommended as the patient was symptomatic from his atrial fibrillation. He subsequently underwent a TEE that excluded both spontaneous echo contrast (SEC) and left atrial appendage thrombi and was successfully cardioverted to normal sinus rhythm. He improved symptomatically after the cardioversion and remained in normal sinus rhythm until 4 weeks later when he presented with recurrence of symptomatic atrial fibrillation. He was initiated on antiarrhythmic therapy with amiodarone and underwent a repeat cardioversion procedure. During the period between the cardioversions, the patient was compliant with his dabigatran 150 mg twice daily. Compliance with his anticoagulation therapy was confirmed with his outpatient pharmacy refill records. A TEE study was not performed prior to this second cardioversion as the patient had been fully anticoagulated for the preceding 4 weeks and as the initial TEE 4 weeks prior was negative for thrombi. The second cardioversion attempt was also successful and the patient was discharged home on dabigatran in normal sinus rhythm. Approximately 72 hours following cardioversion, the patient began having amaurosis fugax in his right eye, which spontaneously resolved. Six hours after that event, he developed left-side hemiplegia and presented to an outlying facility. He was subsequently transferred to our facility where a computed tomography scan revealed an acute right middle cerebral artery infarct. Magnetic resonance angiography demonstrated complete lack of flow in the right middle cerebral artery. His National Institutes of Health Stroke Scale score was 17 out of 42 and he was deemed not a candidate for thrombolytics because of time of onset (>4.5 hours since last known normal) and concurrent dabigatran therapy. Further evaluation of his carotid arteries with magnetic resonance angiography did not reveal any explanations for his stroke. Clinically, it was felt that this patient had suffered a cardioembolic event; however, a repeat TEE showed no evidence of increased left atrial dilation, SEC or left atrial appendage thrombi. Therefore, a noncardiac source, such as carotid artery or cerebral artery thrombosis with possible subsequent embolization, could not be ruled out. The patient’s clinical course was complicated due to his dense left hemiplegia and dysphagia. He required gastrostomy tube placement and was transferred to an inpatient rehabilitation center after a 12-day hospitalization.
Discussion Cardioversion, either chemical or electrical, is used to restore normal sinus rhythm in patients with atrial fibrillation. However, cardioversion is associated with an increased risk of thromboembolic events resulting from dislodged
thrombi originating from the left atrial appendage.4,5 In the 1960s, Bjerkelund and Orning6 performed a nonrandomized, retrospective study of 572 cardioversion patients in which they demonstrated that anticoagulation prior to cardioversion decreased the incidence of thromboembolism by 3.4% (from 4% to 0.67%; P < .05). A more contemporary randomized, controlled trial conducted in 1222 patients (619 patients assigned to TEE-guided approach) demonstrated a comparable risk of thromboembolic events with both the conventional and TEE-guided strategy in patients with atrial fibrillation >2 days in duration (0.50% vs 0.81%; P = .501).7 Black et al8 assessed the risk of postcardioversion embolic events in 17 non-anticoagulated patients in whom atrial thrombi were ruled out with TEE. Of the 17 patients, 5 had SEC prior to cardioversion. Five patients underwent a repeat TEE after the embolic event. Abnormalities were detected in 4 of these 5 patients (1 new atrial thrombus and 3 with new SEC).8 In patients with atrial fibrillation of unknown duration or duration >48 hours, both the American Heart Association and American College of Chest Physicians guidelines recommend therapeutic anticoagulation for at least 3 weeks prior and 4 weeks after cardioversion or the use of TEE to rule out thrombi prior to cardioversion.4,5 Historically, anticoagulation has been achieved with heparin, low-molecular-weight heparins, and/or warfarin; however, dabigatran represents a novel oral anticoagulant option for management of these patients despite not being approved as such.4,5 Nagarakanti et al3 published a post hoc analysis of patients who underwent cardioversion in the RE-LY trial.1,2 TEE was encouraged in all patients with planned cardioversion regardless of randomization to warfarin or dabigatran; however, the ultimate decision regarding medical management was left up to the responsibility of the patient’s primary physician. A total of 1983 cardioversions were performed during the span of the RE-LY trial—647, 672, and 664 in the dabigatran 110 mg, dabigatran 150 mg, and warfarin groups, respectively. More than 75% of patients were on their protocol-assigned study drug for at least 3 weeks prior to cardioversion. There were 2 strokes or systemic embolic events within 30 days of cardioversion in the dabigatran 150 mg twice daily group compared with 4 events in the warfarin group (0.30% vs 0.60% respectively; P = .45). Of the 2 dabigatran 150 mg patients who had events, neither underwent a TEE prior to cardioversion and only 1 was on dabigatran for at least 3 weeks prior to the procedure. Nevertheless, the event rate with dabigatran was comparable to warfarin. There are limited cardioversion data with other novel oral anticoagulants. Fewer than 100 cardioversions were performed in the phase III trial comparing rivaroxaban with warfarin.9 Cardioversion data for 577 patients from a phase III trial comparing apixaban with warfarin demonstrated no ischemic strokes or systemic emboli over a 90-day follow up period.10 Our patient had no
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evidence of thrombi or echo contrast on TEE prior to his first cardioversion, had been compliant with more than 3 weeks of dabigatran therapy, and a low annual risk of stroke. Although no intervention can bring an event rate to zero, an event such as this is troubling. A similar case was published by Buch et al11 from Denmark. These authors describe a 65-year-old man treated with dabigatran for 66 days prior to cardioversion. Five days after cardioversion, the patient developed extensive thrombosis, including cerebral thromboembolism. Since the case is published in Danish, the exact details are unavailable in English; however, this case illustrates the potential risks with dabigatran and cardioversion. The patient appeared to be adherent with dabigatran therapy, as judged by his history and outpatient pharmacy records. His activated partial thromboplastin time was elevated at admission (41.8 seconds), indicating the presence of dabigatran within his serum; however, there are no blood tests to confirm or refute his compliance.12 He was not taking any cytochrome P450 or P-glycoprotein inducers that may have reduced the overall exposure to dabigatran, but was taking a proton pump inhibitor (dexlansoprazole). Dabigatran relies on an acidic pH for absorption and is formulated with tartaric acid pellets to enhance absorption. In pharmacokinetic analyses, concomitant use of proton pump inhibitors has been shown to decrease drug exposure by approximately 25%.13,14 This decrease in exposure was not felt to be clinically significant and was not included as a drug interaction in the package labeling.14 In this patient, the decreased exposure may have contributed to thrombosis during dabigatran therapy. If patients require acid suppressive therapy, it has been suggested to alternate administration times to minimize the potential interaction.15 One potential explanation of this event may be related to the atrial stunning phenomenon associated with all forms of cardioversion. This has been described as a transient loss of contractile function of the atria, resulting in blood stasis and promoting thrombus formation.16 This physiologic state occurs in up to 80% of patients and may last from minutes to months following the cardioversion. During this period, atrial contractility may be reduced by as much as 75% and leads to an increased risk of SEC formation and subsequent thromboembolic disease.16 For these reasons, guidelines recommend continuation of anticoagulation for at least 4 weeks following cardioversion even in patients who convert to normal sinus rhythm. The risk appears to be greater among patients who demonstrate SEC findings on TEE.16 In a study of 140 patients, Fatkin et al17 demonstrated SEC was an independent predictor for atrial thrombus formation and was present in 93% of patients with thrombus. Our patient did not demonstrate left atrial thrombus or SEC, neither on TEE prior to the initial cardioversion nor on the TEE performed 7 hours after arrival to our facility. It is possible that atrial stunning contributed to formation of a thrombus
between cardioversions, though the patient was fully anticoagulated with dabigatran and there was no evidence of stunning on TEE. Another explanation is that the patient did not have a cardioembolic stroke, rather may have developed a carotid or cerebral artery thrombosis in situ due to increased inflammation and platelet functionality. In a meta-analysis of seven trials, when compared with the control treatments (warfarin, enoxaparin, or placebo), dabigatran use resulted in a significantly higher risk of myocardial infarction and acute coronary syndrome (odds ratio vs control = 1.33; 95% confidence interval = 1.03-1.71; P = .03).18 These results were primarily driven by the increased incidence of myocardial infarction in the original RE-LY trial (74% of events in the meta-analysis). A study with ximelagatran, another oral direct thrombin inhibitor that was not Food and Drug Administration approved because of hepatotoxicity, demonstrated increases in pro-inflammatory markers.19 In an open-label study, dabigatran doses of 150 and 300 mg twice daily suppressed d-dimer levels, but urinary 11-dehydrothromboxane B2 was paradoxically increased.20 Although the clinical significance of these increases in platelet functionality and pro-inflammatory mediators is unknown, it is possible that there may be some prothrombotic risk with dabigatran. This has been ill defined in the literature and merits further investigation.
Conclusion We describe a case of ischemic stroke shortly after cardioversion in a treatment-adherent patient on approximately 6 weeks of dabigatran therapy. This duration of therapy was far longer than was described by Nagarakanti et al3 or recommended by guidelines. No drug interactions were identified, except for a potential interaction with his proton pump inhibitor. It is possible this event was not cardiac in origin and may be related to potential pro-inflammatory effects of oral direct thrombin inhibitors. These theoretical mechanisms merit further investigation but should not necessarily preclude the use of this oral anticoagulant in the setting of cardioversion. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Cardiovascular and Renal Drugs Advisory Committee. September 20, 2010. http://www.fda.gov/downloads/
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Faust et al AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM236322.pdf. Accessed July 27, 2013. 2. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:11391151. 3. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011;123:131-136. 4. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians evidence-based clinical practice guidelines. 9th ed. Chest. 2012;141:e531S-e575S. 5. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report from the American College of Cardiology/ American Heart Association task force on practice guidelines and European Society of Cardiology Committee for practice guidelines. J Am Coll Cardiol. 2006;48:e149-e246. 6. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to DC electrical conversion of atrial fibrillation. Am J Cardiol. 1969;23:208-216. 7. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001;344:1411-1420. 8. Black IW, Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study. Circulation. 1994;89:2509-2513. 9. Data on file. Johnson & Johnson Pharmaceutical Research and Development, LLC. 10. Flaker G, Lopes R, Al-Khatib S, et al. Abstract 4048: Apixaban and warfarin are associated with a low risk of stroke following cardioversion for atrial fibrillation: results from the ARISTOTLE trial. Eur Heart J. 2012;33(abstract suppl):686.
11. Buch TN, Holm J, Munck LK. Extensive thromboembolism after cardioversion in a patient treated with dabigatran [in Danish]. Ugeskr Laeger. 2013;175:333-334. 12. Van Ryn J, Stangier J, Haertter, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127. 13. Stangler J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subject. Clin Pharmacokinet. 2008;47:47-59. 14. Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost. 2011;9:2168-2175. 15. Davis EM, Packard KA, Knezevich JT, et al. New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome. Pharmacotherapy. 2011;31:975-1016. 16. Khan IA. Transient atrial mechanical dysfunction (stunning) after cardioversion of atrial fibrillation and flutter. Am Heart J. 2002;144:11-22. 17. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol. 1994;23:961-969. 18. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012;172:397402. 19. Christersson C, Oldgren J, Wallentin L, et al. Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction. J Intern Med. 2011;270:215-223. 20. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol. 2007;100:1419-1426.
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2013
AOPXXX10.1177/1060028013500941Faust et alThe Annals of Pharmacotherapy
Case Report
Acute Ischemic Stroke Following Cardioversion in a Patient Receiving Dabigatran
Annals of Pharmacotherapy 47(10) 1368–1371 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500941 aop.sagepub.com
Andrew C. Faust, PharmD, BCPS1, Megan B. Smith, PharmD, BCPS1,2, and Darryl Kawalsky, MD, FACC, FACP3
Abstract Objective: To report a case of acute ischemic stroke following electrical cardioversion in a patient currently anticoagulated with dabigatran 150 mg twice daily. Case Summary: A 74-year-old man, who had been adherent with more than 6 weeks of dabigatran 150 mg twice daily therapy, presented with a dense left-sided hemiparesis 72 hours following a repeat electrical cardioversion. Both computed tomography and magnetic resonance angiogram confirmed a right middle cerebral artery infarct. A transesophageal echocardiogram performed after the cerebrovascular accident failed to demonstrate a cardiac source of embolus. The patient previously underwent cardioversion 4 weeks prior with no evidence at that time of thrombus or spontaneous echo contrast on transesophageal echocardiogram. Discussion: Dabigatran was approved in the United States in late 2010 for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Post hoc data from the phase III trial suggest a low risk of embolism following cardioversion. Since there are no conventional coagulation measures to reliably demonstrate the level of anticoagulation in patients on dabigatran, clinicians must rely solely on patient history when assessing the safety of cardioverting a patient on this medication. Data have suggested increased pro-inflammatory mediators and increased risk of myocardial infarction with oral direct thrombin inhibitors, which may have manifested as a cerebral or carotid artery thrombosis in situ. Conclusion: Novel oral anticoagulants are attractive options for anticoagulation required with cardioversion. Although this case report may not preclude use of dabigatran for this purpose, it illustrates that use of this drug is not without risks. Additional investigation into the proinflammatory nature of the oral direct thrombin inhibitors is needed. Keywords dabigatran, cardioversion, ischemic stroke
Background
Case Report
Dabigatran etexilate (dabigatran) was approved by the US Food and Drug Administration in late 2010 for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 This approval was based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which found dabigatran 150 mg twice daily to be superior to warfarin with regard to stroke or systemic embolism (relative risk = 0.66; 95% confidence interval = 0.53-0.82; P < .001).2 Post hoc data analysis from RE-LY suggests a low risk of stroke and systemic embolism at 30 days following cardioversion with use of dabigatran 150 mg twice daily.3 Despite the use of transesophageal echocardiography (TEE) and more than 6 weeks of anticoagulation with dabigatran 150 mg twice daily, we describe a patient who suffered an ischemic stroke approximately 72 hours following cardioversion.
The patient is a 74-year-old, 71-kg man with a known history of nonvalvular atrial fibrillation on chronic anticoagulation, coronary artery disease, hypertensive heart disease, and sleep apnea on a home continuous positive airway pressure machine. He presented as an outpatient with recurrent symptomatic atrial fibrillation. Several weeks prior to this outpatient visit, he was converted from warfarin to 1
Texas Health Presbyterian Hospital Dallas, Dallas, TX, USA Texas Tech University Health Science Center, Dallas, TX, USA 3 North Texas Heart Center, Dallas, TX, USA 2
Corresponding Author: Andrew C. Faust, PharmD, BCPS, Department of Pharmacy, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231, USA. Email: [email protected]
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Faust et al dabigatran 150 mg twice daily at his request. The patient’s CHADS2 score was calculated as 1 and his CHA2DS2-VASc score was 3. Electrical cardioversion was recommended as the patient was symptomatic from his atrial fibrillation. He subsequently underwent a TEE that excluded both spontaneous echo contrast (SEC) and left atrial appendage thrombi and was successfully cardioverted to normal sinus rhythm. He improved symptomatically after the cardioversion and remained in normal sinus rhythm until 4 weeks later when he presented with recurrence of symptomatic atrial fibrillation. He was initiated on antiarrhythmic therapy with amiodarone and underwent a repeat cardioversion procedure. During the period between the cardioversions, the patient was compliant with his dabigatran 150 mg twice daily. Compliance with his anticoagulation therapy was confirmed with his outpatient pharmacy refill records. A TEE study was not performed prior to this second cardioversion as the patient had been fully anticoagulated for the preceding 4 weeks and as the initial TEE 4 weeks prior was negative for thrombi. The second cardioversion attempt was also successful and the patient was discharged home on dabigatran in normal sinus rhythm. Approximately 72 hours following cardioversion, the patient began having amaurosis fugax in his right eye, which spontaneously resolved. Six hours after that event, he developed left-side hemiplegia and presented to an outlying facility. He was subsequently transferred to our facility where a computed tomography scan revealed an acute right middle cerebral artery infarct. Magnetic resonance angiography demonstrated complete lack of flow in the right middle cerebral artery. His National Institutes of Health Stroke Scale score was 17 out of 42 and he was deemed not a candidate for thrombolytics because of time of onset (>4.5 hours since last known normal) and concurrent dabigatran therapy. Further evaluation of his carotid arteries with magnetic resonance angiography did not reveal any explanations for his stroke. Clinically, it was felt that this patient had suffered a cardioembolic event; however, a repeat TEE showed no evidence of increased left atrial dilation, SEC or left atrial appendage thrombi. Therefore, a noncardiac source, such as carotid artery or cerebral artery thrombosis with possible subsequent embolization, could not be ruled out. The patient’s clinical course was complicated due to his dense left hemiplegia and dysphagia. He required gastrostomy tube placement and was transferred to an inpatient rehabilitation center after a 12-day hospitalization.
Discussion Cardioversion, either chemical or electrical, is used to restore normal sinus rhythm in patients with atrial fibrillation. However, cardioversion is associated with an increased risk of thromboembolic events resulting from dislodged
thrombi originating from the left atrial appendage.4,5 In the 1960s, Bjerkelund and Orning6 performed a nonrandomized, retrospective study of 572 cardioversion patients in which they demonstrated that anticoagulation prior to cardioversion decreased the incidence of thromboembolism by 3.4% (from 4% to 0.67%; P < .05). A more contemporary randomized, controlled trial conducted in 1222 patients (619 patients assigned to TEE-guided approach) demonstrated a comparable risk of thromboembolic events with both the conventional and TEE-guided strategy in patients with atrial fibrillation >2 days in duration (0.50% vs 0.81%; P = .501).7 Black et al8 assessed the risk of postcardioversion embolic events in 17 non-anticoagulated patients in whom atrial thrombi were ruled out with TEE. Of the 17 patients, 5 had SEC prior to cardioversion. Five patients underwent a repeat TEE after the embolic event. Abnormalities were detected in 4 of these 5 patients (1 new atrial thrombus and 3 with new SEC).8 In patients with atrial fibrillation of unknown duration or duration >48 hours, both the American Heart Association and American College of Chest Physicians guidelines recommend therapeutic anticoagulation for at least 3 weeks prior and 4 weeks after cardioversion or the use of TEE to rule out thrombi prior to cardioversion.4,5 Historically, anticoagulation has been achieved with heparin, low-molecular-weight heparins, and/or warfarin; however, dabigatran represents a novel oral anticoagulant option for management of these patients despite not being approved as such.4,5 Nagarakanti et al3 published a post hoc analysis of patients who underwent cardioversion in the RE-LY trial.1,2 TEE was encouraged in all patients with planned cardioversion regardless of randomization to warfarin or dabigatran; however, the ultimate decision regarding medical management was left up to the responsibility of the patient’s primary physician. A total of 1983 cardioversions were performed during the span of the RE-LY trial—647, 672, and 664 in the dabigatran 110 mg, dabigatran 150 mg, and warfarin groups, respectively. More than 75% of patients were on their protocol-assigned study drug for at least 3 weeks prior to cardioversion. There were 2 strokes or systemic embolic events within 30 days of cardioversion in the dabigatran 150 mg twice daily group compared with 4 events in the warfarin group (0.30% vs 0.60% respectively; P = .45). Of the 2 dabigatran 150 mg patients who had events, neither underwent a TEE prior to cardioversion and only 1 was on dabigatran for at least 3 weeks prior to the procedure. Nevertheless, the event rate with dabigatran was comparable to warfarin. There are limited cardioversion data with other novel oral anticoagulants. Fewer than 100 cardioversions were performed in the phase III trial comparing rivaroxaban with warfarin.9 Cardioversion data for 577 patients from a phase III trial comparing apixaban with warfarin demonstrated no ischemic strokes or systemic emboli over a 90-day follow up period.10 Our patient had no
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evidence of thrombi or echo contrast on TEE prior to his first cardioversion, had been compliant with more than 3 weeks of dabigatran therapy, and a low annual risk of stroke. Although no intervention can bring an event rate to zero, an event such as this is troubling. A similar case was published by Buch et al11 from Denmark. These authors describe a 65-year-old man treated with dabigatran for 66 days prior to cardioversion. Five days after cardioversion, the patient developed extensive thrombosis, including cerebral thromboembolism. Since the case is published in Danish, the exact details are unavailable in English; however, this case illustrates the potential risks with dabigatran and cardioversion. The patient appeared to be adherent with dabigatran therapy, as judged by his history and outpatient pharmacy records. His activated partial thromboplastin time was elevated at admission (41.8 seconds), indicating the presence of dabigatran within his serum; however, there are no blood tests to confirm or refute his compliance.12 He was not taking any cytochrome P450 or P-glycoprotein inducers that may have reduced the overall exposure to dabigatran, but was taking a proton pump inhibitor (dexlansoprazole). Dabigatran relies on an acidic pH for absorption and is formulated with tartaric acid pellets to enhance absorption. In pharmacokinetic analyses, concomitant use of proton pump inhibitors has been shown to decrease drug exposure by approximately 25%.13,14 This decrease in exposure was not felt to be clinically significant and was not included as a drug interaction in the package labeling.14 In this patient, the decreased exposure may have contributed to thrombosis during dabigatran therapy. If patients require acid suppressive therapy, it has been suggested to alternate administration times to minimize the potential interaction.15 One potential explanation of this event may be related to the atrial stunning phenomenon associated with all forms of cardioversion. This has been described as a transient loss of contractile function of the atria, resulting in blood stasis and promoting thrombus formation.16 This physiologic state occurs in up to 80% of patients and may last from minutes to months following the cardioversion. During this period, atrial contractility may be reduced by as much as 75% and leads to an increased risk of SEC formation and subsequent thromboembolic disease.16 For these reasons, guidelines recommend continuation of anticoagulation for at least 4 weeks following cardioversion even in patients who convert to normal sinus rhythm. The risk appears to be greater among patients who demonstrate SEC findings on TEE.16 In a study of 140 patients, Fatkin et al17 demonstrated SEC was an independent predictor for atrial thrombus formation and was present in 93% of patients with thrombus. Our patient did not demonstrate left atrial thrombus or SEC, neither on TEE prior to the initial cardioversion nor on the TEE performed 7 hours after arrival to our facility. It is possible that atrial stunning contributed to formation of a thrombus
between cardioversions, though the patient was fully anticoagulated with dabigatran and there was no evidence of stunning on TEE. Another explanation is that the patient did not have a cardioembolic stroke, rather may have developed a carotid or cerebral artery thrombosis in situ due to increased inflammation and platelet functionality. In a meta-analysis of seven trials, when compared with the control treatments (warfarin, enoxaparin, or placebo), dabigatran use resulted in a significantly higher risk of myocardial infarction and acute coronary syndrome (odds ratio vs control = 1.33; 95% confidence interval = 1.03-1.71; P = .03).18 These results were primarily driven by the increased incidence of myocardial infarction in the original RE-LY trial (74% of events in the meta-analysis). A study with ximelagatran, another oral direct thrombin inhibitor that was not Food and Drug Administration approved because of hepatotoxicity, demonstrated increases in pro-inflammatory markers.19 In an open-label study, dabigatran doses of 150 and 300 mg twice daily suppressed d-dimer levels, but urinary 11-dehydrothromboxane B2 was paradoxically increased.20 Although the clinical significance of these increases in platelet functionality and pro-inflammatory mediators is unknown, it is possible that there may be some prothrombotic risk with dabigatran. This has been ill defined in the literature and merits further investigation.
Conclusion We describe a case of ischemic stroke shortly after cardioversion in a treatment-adherent patient on approximately 6 weeks of dabigatran therapy. This duration of therapy was far longer than was described by Nagarakanti et al3 or recommended by guidelines. No drug interactions were identified, except for a potential interaction with his proton pump inhibitor. It is possible this event was not cardiac in origin and may be related to potential pro-inflammatory effects of oral direct thrombin inhibitors. These theoretical mechanisms merit further investigation but should not necessarily preclude the use of this oral anticoagulant in the setting of cardioversion. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Cardiovascular and Renal Drugs Advisory Committee. September 20, 2010. http://www.fda.gov/downloads/
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