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Acute coronary syndromes and Anagrelide
International Journal of Cardiology 117 (2007) e17 – e19 www.elsevier.com/locate/ijcard
Letter to the Editor
Acute coronary syndromes and Anagrelide Gen-Min Lin a,c , Tsu-Yi Chao b , Wen-Bing Wang a,⁎ a b
Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Division of Hematology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan c Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan Received 15 April 2006; accepted 15 July 2006
Keywords: Anagrelide; Acute coronary syndromes; Coronary vasospasm
To the Editor, Anagrelide is a derivative of quinazoline, whose main action is to inhibit the differentiation of megakaryocytes. It was first used in clinical trials in 1992, along with hydroxyurea, and is widely considered to be a first-line treatment for essential thrombocythemia. Side effects of Anagrelide include mild anemia, gastrointestinal discomfort, headaches, tachyarrhythmias, and fluid retention due to drug-induced vasodilatation and increased myocardial contraction. Acute coronary syndromes were reported rarely in 1–5% patients taking Anagrelide. Herein, we report a case of variant angina caused by Anagrelide presenting as diffuse coronary vasospasm. 1. A case report A 50-year-old woman diagnosed as essential thrombocythemia (ET) in 1993 has been treated with hydroxyurea. Symptoms like parethesia of fingers and acrocynosis were ameliorated after treatment. She started to take low-dose aspirin and sublingual nitroglycerin occasionally for intermittent chest pain since 2001. Anagrelide was added due to progressive elevated platelet counts and its dosage was initiated from 0.5 mg to 1 mg twice daily since March, 2004. In October 2004, she suffered from exertional angina for 2 weeks and was admitted to the Cardiovascular Section in the Tri-Service General Hospital in Taiwan. On admission, the patient's blood pressure was 120/80 mm Hg, heart rate ⁎ Corresponding author. Neihu Main Facility No. 325, sec 2, Cheng-Gong Rd, Neihu Distinct 114, Taipei, Taiwan. E-mail addresses: [email protected] (G.-M. Lin), [email protected] (W.-B. Wang). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.07.079
Fig. 1.
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G.-M. Lin et al. / International Journal of Cardiology 117 (2007) e17–e19
Fig. 2.
was 86 beats/min, and respirations were 14/min. She was alert with no distress. Physical findings on cardiovascular, respiratory, and abdominal examinations were normal. A complete blood count showed a leukocyte count: 5.50 × 103/ μL, a hemoglobin: 11.5 gm/dL, a mean cell volume: 111.7 fL, and a platelet count: 318 × 103/μL. Level of electrolytes were normal. The renal, liver, thyroid function tests and lipid profiles were all within normal range. An electrocardiogram demonstrated T wave inversion in V1–V4. A chest-X-ray film showed normal cardiac size. Subsequently, a coronary angiography demonstrated diffuse small caliber of each coronary arteries. A critical lesion over proximal left anterior descending coronary artery was successfully treated by balloon angioplasty (Fig. 1A). She experienced a sudden onset of chest pain at rest 8 h later after angioplasty and an electrocardiogram showed T wave inversion in V1–V4 (Fig. 2A). Her symptom was improved after the intervention with continuous administration of nitrate intravenously for 3 days. Not only did the symptom subside after discontinuing Anagrelide, but also her electrocardiogram returned to normal (Fig. 2B). She was asymptomatic under medication with hydroxyurea 500 mg three times daily, a long-acting isosorbide-5-mononitrate agent and low-dose aspirin after discharge. A follow-up coronary angiography 2 months later in January 2005 showed a normal size of each coronary artery and no more critical lesions (Fig. 1B).
2. Discussion Anagrelide inhibits type III cyclic adenosine monophosphate (cAMP) phosphodiesterase, which may be responsible for the positive inotropic activity and vasodilatation pharmacologically. Adverse responses are related to its accumulated dosage, dosing interval, and withdrawal. Serious cardiovascular adverse effects were documented clinically, including congestive heart failure, arrhythmia, and acute coronary syndromes [1]. Comparative to alternative findings of coronary angiogram and electrocardiogram with and without Anagrelide, we find that this drug can induce coronary vasospasm directly. This provides us a reason why Anagrelide may cause acute coronary syndromes in some patients [2]. Obviously, there exist other mechanisms contributing to coronary vasospasm than its relaxed effect on vessel smooth muscle. As we know, coronary vasospasm is regulated via coronary endothelium and autonomic nervous system [3]. In some animal models, phosphodiesterase inhibitors have been shown to increase transmitter release from sympathetic nerves and enhance the sympathetic tone [4]. Like sympathomimetic drugs, Anagrelide had positive inotropic and chronotropic impacts on cardiovascular system in clinical observations [1]. Differences in sympathetic effect on epicardial coronary artery are determined by individualized
G.-M. Lin et al. / International Journal of Cardiology 117 (2007) e17–e19
distributions of α- and β-adrenergic receptors which cause coronary vasoconstrictions and vasodilatation, respectively. These could be explained why only a few numbers of patients affected by Anagrelide on coronary artery. In Cacciola et al. study, Anagrelide may lower levels of platelet factor 4 and vascular endothelial growth factor in relation to depressed platelet counts [5]. These growth factors account for the development of collateral vessels and enhance the extent of endothelial regeneration after arterial injury [6]. In other words, Anagrelide may attenuate the ability of coronary neoangiogenesis and further cause myocardial ischemia in the situation of endothelial dysfunction. In our experience with this patient, Anagrelide can provoke coronary vasospasm, which may be attributed to its sympathetic effect and endothelial dysfunction.
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References [1] Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 1992;92:69–76. [2] Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes. Characterization by continuous ST-segment monitoring. Circulation 1997;95:1185–92. [3] Gersh B. Chronic coronary artery disease. Heart Disease: A Textbook of Cardiovascular Medicine 6th edition. 1324–1328. [4] Johnston H, Majewski H, Musgrave IF. Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria. Br J Pharmacol 1987;9:773–81. [5] Cacciola RR, Francesco ED, Giustolisi R, et al. Effects of anagrelide on platelet factor 4 and vascular endothelial growth factor levels in patients with essential thrombocythemia. Br J Haematol 2004;126:885–6. [6] Christophe B. Growth factors as a potential new treatment for ischemic heart disease. Clin Cardiol 1997;20(Suppl II):52–7.
Letter to the Editor
Acute coronary syndromes and Anagrelide Gen-Min Lin a,c , Tsu-Yi Chao b , Wen-Bing Wang a,⁎ a b
Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Division of Hematology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan c Department of Internal Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan Received 15 April 2006; accepted 15 July 2006
Keywords: Anagrelide; Acute coronary syndromes; Coronary vasospasm
To the Editor, Anagrelide is a derivative of quinazoline, whose main action is to inhibit the differentiation of megakaryocytes. It was first used in clinical trials in 1992, along with hydroxyurea, and is widely considered to be a first-line treatment for essential thrombocythemia. Side effects of Anagrelide include mild anemia, gastrointestinal discomfort, headaches, tachyarrhythmias, and fluid retention due to drug-induced vasodilatation and increased myocardial contraction. Acute coronary syndromes were reported rarely in 1–5% patients taking Anagrelide. Herein, we report a case of variant angina caused by Anagrelide presenting as diffuse coronary vasospasm. 1. A case report A 50-year-old woman diagnosed as essential thrombocythemia (ET) in 1993 has been treated with hydroxyurea. Symptoms like parethesia of fingers and acrocynosis were ameliorated after treatment. She started to take low-dose aspirin and sublingual nitroglycerin occasionally for intermittent chest pain since 2001. Anagrelide was added due to progressive elevated platelet counts and its dosage was initiated from 0.5 mg to 1 mg twice daily since March, 2004. In October 2004, she suffered from exertional angina for 2 weeks and was admitted to the Cardiovascular Section in the Tri-Service General Hospital in Taiwan. On admission, the patient's blood pressure was 120/80 mm Hg, heart rate ⁎ Corresponding author. Neihu Main Facility No. 325, sec 2, Cheng-Gong Rd, Neihu Distinct 114, Taipei, Taiwan. E-mail addresses: [email protected] (G.-M. Lin), [email protected] (W.-B. Wang). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.07.079
Fig. 1.
e18
G.-M. Lin et al. / International Journal of Cardiology 117 (2007) e17–e19
Fig. 2.
was 86 beats/min, and respirations were 14/min. She was alert with no distress. Physical findings on cardiovascular, respiratory, and abdominal examinations were normal. A complete blood count showed a leukocyte count: 5.50 × 103/ μL, a hemoglobin: 11.5 gm/dL, a mean cell volume: 111.7 fL, and a platelet count: 318 × 103/μL. Level of electrolytes were normal. The renal, liver, thyroid function tests and lipid profiles were all within normal range. An electrocardiogram demonstrated T wave inversion in V1–V4. A chest-X-ray film showed normal cardiac size. Subsequently, a coronary angiography demonstrated diffuse small caliber of each coronary arteries. A critical lesion over proximal left anterior descending coronary artery was successfully treated by balloon angioplasty (Fig. 1A). She experienced a sudden onset of chest pain at rest 8 h later after angioplasty and an electrocardiogram showed T wave inversion in V1–V4 (Fig. 2A). Her symptom was improved after the intervention with continuous administration of nitrate intravenously for 3 days. Not only did the symptom subside after discontinuing Anagrelide, but also her electrocardiogram returned to normal (Fig. 2B). She was asymptomatic under medication with hydroxyurea 500 mg three times daily, a long-acting isosorbide-5-mononitrate agent and low-dose aspirin after discharge. A follow-up coronary angiography 2 months later in January 2005 showed a normal size of each coronary artery and no more critical lesions (Fig. 1B).
2. Discussion Anagrelide inhibits type III cyclic adenosine monophosphate (cAMP) phosphodiesterase, which may be responsible for the positive inotropic activity and vasodilatation pharmacologically. Adverse responses are related to its accumulated dosage, dosing interval, and withdrawal. Serious cardiovascular adverse effects were documented clinically, including congestive heart failure, arrhythmia, and acute coronary syndromes [1]. Comparative to alternative findings of coronary angiogram and electrocardiogram with and without Anagrelide, we find that this drug can induce coronary vasospasm directly. This provides us a reason why Anagrelide may cause acute coronary syndromes in some patients [2]. Obviously, there exist other mechanisms contributing to coronary vasospasm than its relaxed effect on vessel smooth muscle. As we know, coronary vasospasm is regulated via coronary endothelium and autonomic nervous system [3]. In some animal models, phosphodiesterase inhibitors have been shown to increase transmitter release from sympathetic nerves and enhance the sympathetic tone [4]. Like sympathomimetic drugs, Anagrelide had positive inotropic and chronotropic impacts on cardiovascular system in clinical observations [1]. Differences in sympathetic effect on epicardial coronary artery are determined by individualized
G.-M. Lin et al. / International Journal of Cardiology 117 (2007) e17–e19
distributions of α- and β-adrenergic receptors which cause coronary vasoconstrictions and vasodilatation, respectively. These could be explained why only a few numbers of patients affected by Anagrelide on coronary artery. In Cacciola et al. study, Anagrelide may lower levels of platelet factor 4 and vascular endothelial growth factor in relation to depressed platelet counts [5]. These growth factors account for the development of collateral vessels and enhance the extent of endothelial regeneration after arterial injury [6]. In other words, Anagrelide may attenuate the ability of coronary neoangiogenesis and further cause myocardial ischemia in the situation of endothelial dysfunction. In our experience with this patient, Anagrelide can provoke coronary vasospasm, which may be attributed to its sympathetic effect and endothelial dysfunction.
e19
References [1] Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med 1992;92:69–76. [2] Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes. Characterization by continuous ST-segment monitoring. Circulation 1997;95:1185–92. [3] Gersh B. Chronic coronary artery disease. Heart Disease: A Textbook of Cardiovascular Medicine 6th edition. 1324–1328. [4] Johnston H, Majewski H, Musgrave IF. Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria. Br J Pharmacol 1987;9:773–81. [5] Cacciola RR, Francesco ED, Giustolisi R, et al. Effects of anagrelide on platelet factor 4 and vascular endothelial growth factor levels in patients with essential thrombocythemia. Br J Haematol 2004;126:885–6. [6] Christophe B. Growth factors as a potential new treatment for ischemic heart disease. Clin Cardiol 1997;20(Suppl II):52–7.