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Life-threatening complete atrioventricular block associated with ticagrelor therapy
International Journal of Cardiology 182 (2015) 379–380
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Life-threatening complete atrioventricular block associated with ticagrelor therapy Alexander Goldberg a,b,⁎, Inna Rosenfeld c, Irena Nordkin c, Majdi Halabi b,c a b c
Interventional Cardiology Unit, Ziv Medical Center, Zfat, Israel Faculty of Medicine in Galilee, Bar-Ilan University, Zfat, Israel Department of Cardiology, Ziv Medical Center, Zfat, Israel
a r t i c l e
i n f o
Article history: Received 23 December 2014 Accepted 31 December 2014 Available online 2 January 2015 Keywords: Ticagrelor Bradycardia Atrioventricular block Acute coronary syndrome
Dear Editor, Dual antiplatelet therapy with aspirin and P2Y12 platelet receptor inhibitor is a cornerstone of treatment in acute coronary syndrome (ACS) [1]. Ticagrelor is a novel, potent, direct P2Y12 antagonist with rapid onset of action and intense, consistent platelet reactivity inhibition. In patients with ACS ticagrelor was superior to clopidogrel in decreasing major adverse cardiac events [2]. Therefore, ticagrelor (together with another P2Y12 inhibitor prasugrel) is preferred over clopidogrel [1], and is widely used in the setting of ACS. In the landmark PLATO trial ticagrelor was linked to increased incidence of ventricular pauses which were predominantly asymptomatic [3]. Here we report a case of ticagrelor-associated complete atrioventricular block in a patient with ACS which required resuscitation and insertion of temporary pacemaker. A 52 year old diabetic male patient was admitted to our cardiology department after an episode of a typical anginal chest pain after slight physical activity that lasted about 10 min and resolved after administration of sublingual nitroglycerin. He underwent coronary bypass surgery seven years ago and was asymptomatic prior to admission. He was chronically treated with aspirin, rosuvastatin, bisoprolol and metformin.
⁎ Corresponding author at: Interventional Cardiology, Ziv MC, Zfat, Israel. E-mail address: [email protected] (A. Goldberg).
http://dx.doi.org/10.1016/j.ijcard.2014.12.162 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
At admission the patient was asymptomatic and hemodynamically stable. His admission electrocardiogram showed normal sinus rhythm and complete right bundle brunch block with QRS width of 130 msec. His admission cardiac troponin was normal. His echocardiogram demonstrated preserved left ventricular function with a small akinetic area in basal and mid anterior septum. With initial diagnosis of unstable angina he received a loading dose of clopidogrel and fondaparinux. His regular medical treatment was continued as well. On the second hospitalization day the patient remained asymptomatic but repeated troponin I test was positive at 11 ng/mL and the patient was diagnosed with non ST-elevation myocardial infarction. The same morning a cardiac catheterization was performed that revealed severe stenosis in the distal left main coronary artery, ostial LAD and large ramus. LIMA to LAD was patent; however RIMA to ramus was occluded. Coronary angioplasty with implantation of bare metal stent to distal LM and ramus was successfully performed with a good angiographic result. After the procedure the patient was asymptomatic and hemodynamically stable. His ECG was similar to the admission tracing. Given a high GRACE score and in keeping with current guidelines [1,4] we decided to switch the P2Y12 inhibitor from clopidogrel to ticagrelor. Therefore, the patient received a loading dose of 180 mg ticagrelor. There was no change in his other medications. Four hours later, short episodes of complete atrioventricular block appeared on continuous ECG monitoring. Shortly after that, the patient experienced syncope with ventricular pause of 11 s. After regaining consciousness he complained on severe weakness and dizziness. His heart rhythm now was 30 beats per minute and on ECG there was complete atrioventricular block. He received bolus of 1 mg of atropine and dopamine infusion without any improvement, therefore emergency insertion of a temporary pacemaker was performed and right ventricular pacing was initiated with immediate hemodynamic and symptomatic improvement. The treatment with ticagrelor was stopped and clopidogrel was restarted. The patient remained dependent on pacing for the next two days with underlying rhythm of complete atrioventricular block with ventricular escape of 30 beats per minute. On the third day the patient was mainly in normal sinus rhythm with episodes of complete atrioventricular block and starting from the fourth day there was a stable sinus rhythm with no recurrences of heart block and the temporary pacemaker was removed. The patient was discharged in good clinical condition and during six months of follow up there were no recurrences of heart block or any other bradyarrhythmias.
380
A. Goldberg et al. / International Journal of Cardiology 182 (2015) 379–380
Although the increased incidence of ventricular pauses associated with ticagrelor treatment has been previously reported, it is generally believed to be of no clinical importance [3]. Here we report a patient who developed severe symptomatic bradycardia with complete atrioventricular block after receiving a recommended loading dose of ticagrelor. The patient was unresponsive to medical treatment and required invasive temporary pacing. The atrioventricular block resolved completely after the discontinuation of the drug. To the best of our knowledge this is the first detailed report of life-threatening bradyarrhythmic complication of ticagrelor therapy in a clinical setting; however, sinus arrest with high-degree atrioventricular block did occur in a healthy volunteer after receiving a large dose of ticagrelor in one dose-finding study [5]. Our patient had pre-existing conduction disturbance (CRBBB) and was on chronic beta-blocker therapy that could potentiate the influence of ticagrelor on cardiac conduction; although none of these is considered contraindication to ticagrelor therapy. Also, many patients with acute coronary syndrome receive betablockers and conduction disturbances are not rare in this population. The mechanism of bradyarrhythmic effect of ticagrelor is poorly understood [3]. One possibility is a direct effect of ticagrelor on cardiac automaticity and conduction. The other one implicates an adenosinemediated effect. Ticagrelor inhibits cellular uptake and increases plasma concentration of adenosine [6], which has a potent atrioventricularblocking effect. As such, adenosine is widely used as a diagnostic and therapeutic agent (e.g., in patients with supraventricular tachycardia). Therefore, increase in adenosine levels in patient treated with ticagrelor could be a plausible explanation for its effect on cardiac conduction. Our case demonstrates that bradyarrhythmic effects of ticagrelor can have important (although rare) clinical consequences. We would advise
caution and careful observation of patients after initiating of ticagrelor therapy, especially in patients with already compromised conduction system or treated with medications with atrioventricular blocking properties. References [1] C.W. Hamm, J.-P. Bassand, S. Agewall, J. Bax, E. Boersma, H. Bueno, et al., ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation, Eur. Heart J. 32 (2011) 2999–3054. http://dx.doi.org/10.1093/eurheartj/ehr236. [2] C. Held, N. Asenblad, J.P. Bassand, R.C. Becker, C.P. Cannon, M.J. Claeys, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial, J. Am. Coll. Cardiol. 57 (2011) 672–684. http://dx.doi.org/10.1016/ j.jacc.2010.10.029. [3] B.M. Scirica, C.P. Cannon, H. Emanuelsson, E.L. Michelson, R.a. Harrington, S. Husted, et al., The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiogram, J. Am. Coll. Cardiol. 57 (2011) 1908–1916. http://dx.doi.org/10.1016/ j.jacc.2010.11.056. [4] S. Windecker, P. Kolh, F. Alfonso, J.-P. Collet, J. Cremer, V. Falk, et al., 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) * Developed with the special contribution, Eur. Heart J. (2014). http://dx.doi.org/10.1093/eurheartj/ehu278. [5] R. Teng, K. Butler, Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers, Int. J. Clin. Pharmacol. Ther. 51 (2013) 795–806. http://dx.doi.org/10.5414/CP201903. [6] L. Bonello, M. Laine, N. Kipson, J. Mancini, O. Helal, J. Fromonot, et al., Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome, J. Am. Coll. Cardiol. 63 (2014) 872–877. http://dx.doi.org/10.1016/ j.jacc.2013.09.067.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Life-threatening complete atrioventricular block associated with ticagrelor therapy Alexander Goldberg a,b,⁎, Inna Rosenfeld c, Irena Nordkin c, Majdi Halabi b,c a b c
Interventional Cardiology Unit, Ziv Medical Center, Zfat, Israel Faculty of Medicine in Galilee, Bar-Ilan University, Zfat, Israel Department of Cardiology, Ziv Medical Center, Zfat, Israel
a r t i c l e
i n f o
Article history: Received 23 December 2014 Accepted 31 December 2014 Available online 2 January 2015 Keywords: Ticagrelor Bradycardia Atrioventricular block Acute coronary syndrome
Dear Editor, Dual antiplatelet therapy with aspirin and P2Y12 platelet receptor inhibitor is a cornerstone of treatment in acute coronary syndrome (ACS) [1]. Ticagrelor is a novel, potent, direct P2Y12 antagonist with rapid onset of action and intense, consistent platelet reactivity inhibition. In patients with ACS ticagrelor was superior to clopidogrel in decreasing major adverse cardiac events [2]. Therefore, ticagrelor (together with another P2Y12 inhibitor prasugrel) is preferred over clopidogrel [1], and is widely used in the setting of ACS. In the landmark PLATO trial ticagrelor was linked to increased incidence of ventricular pauses which were predominantly asymptomatic [3]. Here we report a case of ticagrelor-associated complete atrioventricular block in a patient with ACS which required resuscitation and insertion of temporary pacemaker. A 52 year old diabetic male patient was admitted to our cardiology department after an episode of a typical anginal chest pain after slight physical activity that lasted about 10 min and resolved after administration of sublingual nitroglycerin. He underwent coronary bypass surgery seven years ago and was asymptomatic prior to admission. He was chronically treated with aspirin, rosuvastatin, bisoprolol and metformin.
⁎ Corresponding author at: Interventional Cardiology, Ziv MC, Zfat, Israel. E-mail address: [email protected] (A. Goldberg).
http://dx.doi.org/10.1016/j.ijcard.2014.12.162 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
At admission the patient was asymptomatic and hemodynamically stable. His admission electrocardiogram showed normal sinus rhythm and complete right bundle brunch block with QRS width of 130 msec. His admission cardiac troponin was normal. His echocardiogram demonstrated preserved left ventricular function with a small akinetic area in basal and mid anterior septum. With initial diagnosis of unstable angina he received a loading dose of clopidogrel and fondaparinux. His regular medical treatment was continued as well. On the second hospitalization day the patient remained asymptomatic but repeated troponin I test was positive at 11 ng/mL and the patient was diagnosed with non ST-elevation myocardial infarction. The same morning a cardiac catheterization was performed that revealed severe stenosis in the distal left main coronary artery, ostial LAD and large ramus. LIMA to LAD was patent; however RIMA to ramus was occluded. Coronary angioplasty with implantation of bare metal stent to distal LM and ramus was successfully performed with a good angiographic result. After the procedure the patient was asymptomatic and hemodynamically stable. His ECG was similar to the admission tracing. Given a high GRACE score and in keeping with current guidelines [1,4] we decided to switch the P2Y12 inhibitor from clopidogrel to ticagrelor. Therefore, the patient received a loading dose of 180 mg ticagrelor. There was no change in his other medications. Four hours later, short episodes of complete atrioventricular block appeared on continuous ECG monitoring. Shortly after that, the patient experienced syncope with ventricular pause of 11 s. After regaining consciousness he complained on severe weakness and dizziness. His heart rhythm now was 30 beats per minute and on ECG there was complete atrioventricular block. He received bolus of 1 mg of atropine and dopamine infusion without any improvement, therefore emergency insertion of a temporary pacemaker was performed and right ventricular pacing was initiated with immediate hemodynamic and symptomatic improvement. The treatment with ticagrelor was stopped and clopidogrel was restarted. The patient remained dependent on pacing for the next two days with underlying rhythm of complete atrioventricular block with ventricular escape of 30 beats per minute. On the third day the patient was mainly in normal sinus rhythm with episodes of complete atrioventricular block and starting from the fourth day there was a stable sinus rhythm with no recurrences of heart block and the temporary pacemaker was removed. The patient was discharged in good clinical condition and during six months of follow up there were no recurrences of heart block or any other bradyarrhythmias.
380
A. Goldberg et al. / International Journal of Cardiology 182 (2015) 379–380
Although the increased incidence of ventricular pauses associated with ticagrelor treatment has been previously reported, it is generally believed to be of no clinical importance [3]. Here we report a patient who developed severe symptomatic bradycardia with complete atrioventricular block after receiving a recommended loading dose of ticagrelor. The patient was unresponsive to medical treatment and required invasive temporary pacing. The atrioventricular block resolved completely after the discontinuation of the drug. To the best of our knowledge this is the first detailed report of life-threatening bradyarrhythmic complication of ticagrelor therapy in a clinical setting; however, sinus arrest with high-degree atrioventricular block did occur in a healthy volunteer after receiving a large dose of ticagrelor in one dose-finding study [5]. Our patient had pre-existing conduction disturbance (CRBBB) and was on chronic beta-blocker therapy that could potentiate the influence of ticagrelor on cardiac conduction; although none of these is considered contraindication to ticagrelor therapy. Also, many patients with acute coronary syndrome receive betablockers and conduction disturbances are not rare in this population. The mechanism of bradyarrhythmic effect of ticagrelor is poorly understood [3]. One possibility is a direct effect of ticagrelor on cardiac automaticity and conduction. The other one implicates an adenosinemediated effect. Ticagrelor inhibits cellular uptake and increases plasma concentration of adenosine [6], which has a potent atrioventricularblocking effect. As such, adenosine is widely used as a diagnostic and therapeutic agent (e.g., in patients with supraventricular tachycardia). Therefore, increase in adenosine levels in patient treated with ticagrelor could be a plausible explanation for its effect on cardiac conduction. Our case demonstrates that bradyarrhythmic effects of ticagrelor can have important (although rare) clinical consequences. We would advise
caution and careful observation of patients after initiating of ticagrelor therapy, especially in patients with already compromised conduction system or treated with medications with atrioventricular blocking properties. References [1] C.W. Hamm, J.-P. Bassand, S. Agewall, J. Bax, E. Boersma, H. Bueno, et al., ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation, Eur. Heart J. 32 (2011) 2999–3054. http://dx.doi.org/10.1093/eurheartj/ehr236. [2] C. Held, N. Asenblad, J.P. Bassand, R.C. Becker, C.P. Cannon, M.J. Claeys, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial, J. Am. Coll. Cardiol. 57 (2011) 672–684. http://dx.doi.org/10.1016/ j.jacc.2010.10.029. [3] B.M. Scirica, C.P. Cannon, H. Emanuelsson, E.L. Michelson, R.a. Harrington, S. Husted, et al., The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiogram, J. Am. Coll. Cardiol. 57 (2011) 1908–1916. http://dx.doi.org/10.1016/ j.jacc.2010.11.056. [4] S. Windecker, P. Kolh, F. Alfonso, J.-P. Collet, J. Cremer, V. Falk, et al., 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) * Developed with the special contribution, Eur. Heart J. (2014). http://dx.doi.org/10.1093/eurheartj/ehu278. [5] R. Teng, K. Butler, Safety, tolerability, pharmacokinetics and pharmacodynamics of high single-ascending doses of ticagrelor in healthy volunteers, Int. J. Clin. Pharmacol. Ther. 51 (2013) 795–806. http://dx.doi.org/10.5414/CP201903. [6] L. Bonello, M. Laine, N. Kipson, J. Mancini, O. Helal, J. Fromonot, et al., Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome, J. Am. Coll. Cardiol. 63 (2014) 872–877. http://dx.doi.org/10.1016/ j.jacc.2013.09.067.