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Acute coronary syndrome (ACS) in patients with essential thrombocytemia (ET). What is the best treatment?
International Journal of Cardiology 203 (2016) 225–227
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Acute coronary syndrome (ACS) in patients with essential thrombocytemia (ET). What is the best treatment? G. Tortorella a, M. Calzolari a,⁎, A. Tieghi b, N. Muià a, A. Piccin c, L. Gugliotta d a
Cardiology Unit, Azienda Ospedaliera Santa Maria Nuova-IRCCS Reggio Emilia, Italy Hematology Unit, Azienda Ospedaliera Santa Maria Nuova-IRCCS Reggio Emilia, Italy Hematology Unit, San MaurizioRregional Hospital, Bolzano, South Tyrol, Italy d Hematology Institute L.e A. Serignoli S.Orsola Malpighi University Hospital, Bologna, Italy b c
a r t i c l e
i n f o
Article history: Received 21 September 2015 Accepted 4 October 2015 Available online 9 October 2015 Keywords: Essential thrombocythemia Anagrelide Acute coronary syndrome
ET is a chronic myeloproliferative disease characterized by uncontrolled proliferation of piastrinopoietic and persistent piastrinosis. Thrombotic events, mostly arterial, complicates the disease in about 10–25% of cases [1]. Acute coronary syndrome occurs in 9% of patients [2] with underlying multiple pathogenetic mechanisms: coronary thrombosis, vasospasm, and atherothrombosis. The most likely pathogenesis is atherosclerosis [3]. The cytoreduction is associated with significant reduction of thrombotic complications [4]. The guidelines recommend first-line use of Hydroxyurea (HU). By virtue of its potential leukemogenics, anagrelide is considered an effective alternative especially in younger subjects but it's positive inotropic and chronotropic effects raise some concerns about their use during and after ACS. A 55 year old man, with no cardiovascular history affected by ET and already in combined treatment with HU and anagrelide, was hospitalized in March 2012 for chest pain and ECG documentation of “ST-elevation” in D2-D3-aVF (Fig. 1). About 6 months before admission because of a difficult control of his platelet count despite high doses of HU (up to 2 g/day) a combination therapy with anagrelide was started. A preliminary cardiac evaluation did not reveal contraindication to starting the drug and a rigorous control of multiple cardiovascular risk factors (arterial hypertension, dyslipidemia, smoking and obesity) was
⁎ Corresponding author at: Cardiovascular–Thoracic Dipertment, Santa Maria Nuova Hospital/IRCCS, Viale Risorgimento 80, Reggio Emilia, Italy. E-mail address: [email protected] (M. Calzolari).
http://dx.doi.org/10.1016/j.ijcard.2015.10.043 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
strongly recommended. Antihypertensive therapy was ongoing with full doses of zofenopril and a statin was prescribed; antiplatelet therapy was already underway with ticlopidine. Upon entering the CCU chest pain vanished, as well as changes in ECG. There were no signs of heart failure. The BP was 120/80 with 65 bpm. The echocardiogram showed a normal left ventricular ejection fraction without changes in segmental kinetics. The PTL totaled 568,000 mic/L, Hb was 13.4 gr% and Tn I 0.9 ng/ml. The patient was treated with nitrate infusion (started in the ER), oral aspirin (300 mg), tirofiban (given before coronary angiography and 24 h thereafter) and unfractionated heparin. The coronary angiography, performed 2 h later for recurrence of angina, revealed: subocclusive thrombotic stenosis on Right Coronary Artery (RCA) (see Fig. 2), critical stenosis on Left Anterior Descending and MO1. RCA was successfully treated by thromboaspiration, angioplasty and stenting (BMS, LIBERTE′ MONORAIL 32 × 3.5 mm). Therapy with aspirin 100 mg once daily and Ticlopidine 250 mg BID was continued and we started antiischemic therapy with beta blockers and transdermal nitrates. We also confirmed cytoreductive therapy with HU (3 cp) and anagrelide (cp 2–3 days). The patient was discharged on day 5. The platelet count at discharge was 376,000 and Hb was 12.8 g/dl. A stress-echocardiography after 3 months, resulted negative for residual ischemia, especially in the anterior region. Our case suggests that even in ET the most likely pathogenetic mechanism is always atherosclerosis, with coronary thrombosis unleashed by plaque rupture. The “thrombogenic” burden of ET amplify the role of traditional cardiovascular risk factors which also affect the genesis and progression of atherosclerotic vascular disease, involving, along with the age, previous history of thrombotic events and platelet count, a key role in categorizing the thrombotic risk of individual patient [5,6]. It forces hematologists and cardiologists to an accurate individual thrombotic risk stratification in ET patients in order to quantify the risk of developing a major CV event using e.g. the ESC risk cards, and to adopt, even in primary prevention all the measures in order to lower the overall risk of cardiovascular disease [7]. Current very aggressive treatment approach to ACS raises the question of what's the optimal antithrombotic treatment in ET patients suffering an ACS. In our case the approach was in tune with current guideline recommendations [8], maintaining double antiplatelet therapy (DAPT) with aspirin 100 mg daily and ticlopidine 250 mg B.I.D. in post-procedural phases. In order to reduce DAPT duration we used a
226
G. Tortorella et al. / International Journal of Cardiology 203 (2016) 225–227
Fig. 1. Initial ECG showing ST elevation in inferior leads.
bare metal stent (BMS). There were no bleeding complications, neither during hospitalization nor during the subsequent follow-up (12 months). Given the scarce effect on platelet count already demonstrated by HU alone and considering the important role that cytoreductive therapy has in controlling thrombotic complications of ET, ANA was associated to HU. Anagrelide is a potent inhibitor of phosphodiesterase III having a peculiar platelet thrombocytopenic effect, associated with various
effects on the cardiovascular system such as vasodilation and increased inotropism and chronotropism. The drug can have some “adverse” effects on cardiovascular system, most commonly palpitations, tachycardia and edema [9]. Anagrelide use during and after an ACS, namely if undergoing reperfusion strategy, is not contraindicated if left ventricular contractile function is preserved and all the appropriate measures are adopted in heart rate (target 50–60 bpm) and BP control. Among the “antiischemic” drugs, which are able to reduce myocardial oxygen consumption, the role of beta blockers is supported by all guidelines. Conclusion Patients with ET who develop an ACS have a profile similar to “traditional” patients with significant risk factors and coronary atherosclerotic disease. The treatment of choice in such patients is percutaneous reperfusion associated with aggressive antithrombotic treatment and rigorous treatment of vascular risk factors. The cytoreduction is associated with significant reduction of thrombotic complications. Hydroxyurea is recommended as first-line treatment while anagrelide is recommended as second-line medication, especially in younger patients because of lack of leucemogenic effects. Its use during and after an ACS is not contraindicated if the residual left ventricular function is normal and effective antiischemic treatment and beta blockers are started. Conflict of interest Giovanni Tortorella, Massimo Calzolari, Andrea Piccin and Luigi Gugliotta are consultants of Shire Pharmaceuticals as speaker and as member of the EXELS study Steering Committee. References
Fig. 2. Coronary angiography that revealed subocclusive thrombotic stenosis on Right Coronary Artery (RCA).
[1] C. Besses, F. Cervantes, A. Pereira, et al., Major vascular complications in essential thrombocytemia: a study of the predictive factors in a series of 148 patients, Leukemia 13 (1999) 150–154.
G. Tortorella et al. / International Journal of Cardiology 203 (2016) 225–227 [2] C. Rossi, M.L. Randi, P. Zerbinati, V. Rinaldi, A. Girolami, Acute coronary disease in essential thrombocythemia and polycythemia vera, J. Int. Med. 244 (1998) 49–53. [3] R. Prieto, M. Martinez-Selles, F. Fernadez-Aviles, Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events, Acute Card. Care 10 (2008) 116–120. [4] S. Cortellazzo, G. Finazzi, M. Ruggeri, et al., Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis, N. Engl. J. Med. 332 (1995) 1132–1136. [5] A. Carobbio, J. Thiele, F. Passamonti, et al., Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an International study of 891 patients, Blood 117 (22) (2011) 5857–5859. [6] M.A. Elliot, A. Tefferi, Thrombosis and haemorrhage in polycytaemia vera and essential thrombocythaemia, Br. J. Haematol. 128 (2004) 275–290. [7] J. Perk, G. De Backer, H. Gohlke, I. Graham, Z. Reiner, et al., European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint
227
Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR), Eur. Heart J. 33 (2012) 1635–1670. [8] S. Windecker, P. Kolh, F. Alonso, 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), Eur. Heart J. 35 (2014) 2541–2619. [9] L. Gugliotta, A. Thieghi, G. Tortorella, et al., Low impact of cardiovascular adverse events on anagrelide treatment discontinuation in a cohort of 232 patients with essential thrombocythemia, Leuk. Res. 35 (2011) 1557–1563.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Acute coronary syndrome (ACS) in patients with essential thrombocytemia (ET). What is the best treatment? G. Tortorella a, M. Calzolari a,⁎, A. Tieghi b, N. Muià a, A. Piccin c, L. Gugliotta d a
Cardiology Unit, Azienda Ospedaliera Santa Maria Nuova-IRCCS Reggio Emilia, Italy Hematology Unit, Azienda Ospedaliera Santa Maria Nuova-IRCCS Reggio Emilia, Italy Hematology Unit, San MaurizioRregional Hospital, Bolzano, South Tyrol, Italy d Hematology Institute L.e A. Serignoli S.Orsola Malpighi University Hospital, Bologna, Italy b c
a r t i c l e
i n f o
Article history: Received 21 September 2015 Accepted 4 October 2015 Available online 9 October 2015 Keywords: Essential thrombocythemia Anagrelide Acute coronary syndrome
ET is a chronic myeloproliferative disease characterized by uncontrolled proliferation of piastrinopoietic and persistent piastrinosis. Thrombotic events, mostly arterial, complicates the disease in about 10–25% of cases [1]. Acute coronary syndrome occurs in 9% of patients [2] with underlying multiple pathogenetic mechanisms: coronary thrombosis, vasospasm, and atherothrombosis. The most likely pathogenesis is atherosclerosis [3]. The cytoreduction is associated with significant reduction of thrombotic complications [4]. The guidelines recommend first-line use of Hydroxyurea (HU). By virtue of its potential leukemogenics, anagrelide is considered an effective alternative especially in younger subjects but it's positive inotropic and chronotropic effects raise some concerns about their use during and after ACS. A 55 year old man, with no cardiovascular history affected by ET and already in combined treatment with HU and anagrelide, was hospitalized in March 2012 for chest pain and ECG documentation of “ST-elevation” in D2-D3-aVF (Fig. 1). About 6 months before admission because of a difficult control of his platelet count despite high doses of HU (up to 2 g/day) a combination therapy with anagrelide was started. A preliminary cardiac evaluation did not reveal contraindication to starting the drug and a rigorous control of multiple cardiovascular risk factors (arterial hypertension, dyslipidemia, smoking and obesity) was
⁎ Corresponding author at: Cardiovascular–Thoracic Dipertment, Santa Maria Nuova Hospital/IRCCS, Viale Risorgimento 80, Reggio Emilia, Italy. E-mail address: [email protected] (M. Calzolari).
http://dx.doi.org/10.1016/j.ijcard.2015.10.043 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
strongly recommended. Antihypertensive therapy was ongoing with full doses of zofenopril and a statin was prescribed; antiplatelet therapy was already underway with ticlopidine. Upon entering the CCU chest pain vanished, as well as changes in ECG. There were no signs of heart failure. The BP was 120/80 with 65 bpm. The echocardiogram showed a normal left ventricular ejection fraction without changes in segmental kinetics. The PTL totaled 568,000 mic/L, Hb was 13.4 gr% and Tn I 0.9 ng/ml. The patient was treated with nitrate infusion (started in the ER), oral aspirin (300 mg), tirofiban (given before coronary angiography and 24 h thereafter) and unfractionated heparin. The coronary angiography, performed 2 h later for recurrence of angina, revealed: subocclusive thrombotic stenosis on Right Coronary Artery (RCA) (see Fig. 2), critical stenosis on Left Anterior Descending and MO1. RCA was successfully treated by thromboaspiration, angioplasty and stenting (BMS, LIBERTE′ MONORAIL 32 × 3.5 mm). Therapy with aspirin 100 mg once daily and Ticlopidine 250 mg BID was continued and we started antiischemic therapy with beta blockers and transdermal nitrates. We also confirmed cytoreductive therapy with HU (3 cp) and anagrelide (cp 2–3 days). The patient was discharged on day 5. The platelet count at discharge was 376,000 and Hb was 12.8 g/dl. A stress-echocardiography after 3 months, resulted negative for residual ischemia, especially in the anterior region. Our case suggests that even in ET the most likely pathogenetic mechanism is always atherosclerosis, with coronary thrombosis unleashed by plaque rupture. The “thrombogenic” burden of ET amplify the role of traditional cardiovascular risk factors which also affect the genesis and progression of atherosclerotic vascular disease, involving, along with the age, previous history of thrombotic events and platelet count, a key role in categorizing the thrombotic risk of individual patient [5,6]. It forces hematologists and cardiologists to an accurate individual thrombotic risk stratification in ET patients in order to quantify the risk of developing a major CV event using e.g. the ESC risk cards, and to adopt, even in primary prevention all the measures in order to lower the overall risk of cardiovascular disease [7]. Current very aggressive treatment approach to ACS raises the question of what's the optimal antithrombotic treatment in ET patients suffering an ACS. In our case the approach was in tune with current guideline recommendations [8], maintaining double antiplatelet therapy (DAPT) with aspirin 100 mg daily and ticlopidine 250 mg B.I.D. in post-procedural phases. In order to reduce DAPT duration we used a
226
G. Tortorella et al. / International Journal of Cardiology 203 (2016) 225–227
Fig. 1. Initial ECG showing ST elevation in inferior leads.
bare metal stent (BMS). There were no bleeding complications, neither during hospitalization nor during the subsequent follow-up (12 months). Given the scarce effect on platelet count already demonstrated by HU alone and considering the important role that cytoreductive therapy has in controlling thrombotic complications of ET, ANA was associated to HU. Anagrelide is a potent inhibitor of phosphodiesterase III having a peculiar platelet thrombocytopenic effect, associated with various
effects on the cardiovascular system such as vasodilation and increased inotropism and chronotropism. The drug can have some “adverse” effects on cardiovascular system, most commonly palpitations, tachycardia and edema [9]. Anagrelide use during and after an ACS, namely if undergoing reperfusion strategy, is not contraindicated if left ventricular contractile function is preserved and all the appropriate measures are adopted in heart rate (target 50–60 bpm) and BP control. Among the “antiischemic” drugs, which are able to reduce myocardial oxygen consumption, the role of beta blockers is supported by all guidelines. Conclusion Patients with ET who develop an ACS have a profile similar to “traditional” patients with significant risk factors and coronary atherosclerotic disease. The treatment of choice in such patients is percutaneous reperfusion associated with aggressive antithrombotic treatment and rigorous treatment of vascular risk factors. The cytoreduction is associated with significant reduction of thrombotic complications. Hydroxyurea is recommended as first-line treatment while anagrelide is recommended as second-line medication, especially in younger patients because of lack of leucemogenic effects. Its use during and after an ACS is not contraindicated if the residual left ventricular function is normal and effective antiischemic treatment and beta blockers are started. Conflict of interest Giovanni Tortorella, Massimo Calzolari, Andrea Piccin and Luigi Gugliotta are consultants of Shire Pharmaceuticals as speaker and as member of the EXELS study Steering Committee. References
Fig. 2. Coronary angiography that revealed subocclusive thrombotic stenosis on Right Coronary Artery (RCA).
[1] C. Besses, F. Cervantes, A. Pereira, et al., Major vascular complications in essential thrombocytemia: a study of the predictive factors in a series of 148 patients, Leukemia 13 (1999) 150–154.
G. Tortorella et al. / International Journal of Cardiology 203 (2016) 225–227 [2] C. Rossi, M.L. Randi, P. Zerbinati, V. Rinaldi, A. Girolami, Acute coronary disease in essential thrombocythemia and polycythemia vera, J. Int. Med. 244 (1998) 49–53. [3] R. Prieto, M. Martinez-Selles, F. Fernadez-Aviles, Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events, Acute Card. Care 10 (2008) 116–120. [4] S. Cortellazzo, G. Finazzi, M. Ruggeri, et al., Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis, N. Engl. J. Med. 332 (1995) 1132–1136. [5] A. Carobbio, J. Thiele, F. Passamonti, et al., Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an International study of 891 patients, Blood 117 (22) (2011) 5857–5859. [6] M.A. Elliot, A. Tefferi, Thrombosis and haemorrhage in polycytaemia vera and essential thrombocythaemia, Br. J. Haematol. 128 (2004) 275–290. [7] J. Perk, G. De Backer, H. Gohlke, I. Graham, Z. Reiner, et al., European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint
227
Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR), Eur. Heart J. 33 (2012) 1635–1670. [8] S. Windecker, P. Kolh, F. Alonso, 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), Eur. Heart J. 35 (2014) 2541–2619. [9] L. Gugliotta, A. Thieghi, G. Tortorella, et al., Low impact of cardiovascular adverse events on anagrelide treatment discontinuation in a cohort of 232 patients with essential thrombocythemia, Leuk. Res. 35 (2011) 1557–1563.