Long‐term outcome after percutaneous coronary intervention in patients with essential thrombocythemia
2009; Elsevier BV; Volume: 7; Issue: 7 Linguagem: Inglês
10.1111/j.1538-7836.2009.03469.x
ISSN1538-7933
AutoresGianluca Campo, Marco Valgimigli, Roberto Carletti, Luca Fileti, Roberto Ferrari,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoEssential thrombocythemia (ET) is an acquired myeloproliferative disorder that is characterized by increased platelet counts and elevated numbers of hyperploid megakaryocytes in the bone marrow [1Briere J.B. Essential thrombocythemia.Orphanet J Rare Dis. 2007; 2: 3-20Crossref PubMed Scopus (81) Google Scholar]. The major complications associated with ET are thrombotic events (predominantly in the arterial system) and hemorrhagic events, particularly in those patients with very high platelet counts [1Briere J.B. Essential thrombocythemia.Orphanet J Rare Dis. 2007; 2: 3-20Crossref PubMed Scopus (81) Google Scholar]. As ET is most frequently found in elderly patients, the presence of coronary artery disease that requires antiplatelet treatment and coronary revascularization is also common. There are case reports of one or, at most, two patients with hemorrhagic, neurologic or adverse coronary events and ET, but the real frequencies of bleeding and ischemic complications in ET patients who undergo percutaneous coronary intervention (PCI) remain unknown [2Ozben B. Ekmekci A. Bugra Z. Umman S. Meric M. Multiple coronary thrombosis and stent implantation to the subtotally occluded right renal artery in a patient with essential thrombocytosis: a case report with review.J Thromb Thrombolysis. 2006; 22: 79-84Crossref PubMed Scopus (25) Google Scholar, 3Doesch C. Krämer B. Geisler T. May A.E. Kroeber S.M. Kandolf R. Gawaz M. Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome.J Thromb Thrombolysis. 2008; 25: 193-7Crossref PubMed Scopus (8) Google Scholar, 4Prieto R. Mart?nez‐Sellés M. Fernández‐Avilés F. Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events.Acute Card Care. 2008; 10: 116-20Crossref PubMed Scopus (0) Google Scholar]. We present the long‐term follow‐up of 17 patients with ET who underwent coronary artery angiography (CAA) in our cath‐lab, illustrating the medical and interventional management, their responsiveness to oral antiplatelet treatment, and their clinical outcome. From January 2005 to December 2008, 4779 patients were admitted to our cath‐lab (Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy) and scheduled for CAA. Seventeen (0.3%) of these patients were diagnosed with ET and attended regular hematology outpatients’ clinics. All patients received cytoreductive treatment. The mean time from ET diagnosis to CAA was 4.8 ± 2 years (range, 1–9 years). At least 1 month after discharge, all patients returned for evaluation of steady‐state responsiveness to aspirin and clopidogrel. For this purpose, a single blood sample was collected, and antiplatelet therapy response was measured with a Platelet Function Analyzer 100 (PFA‐100) [5Campo G. Valgimigli M. Frangione A. Tebaldi M. Ferrari R. Prognostic value of serial platelet reactivity measurements on long‐term clinical outcome in patients with ST‐elevation myocardial infarction undergoing primary PCI.J Thromb Haemost. 2008; 6: 1824-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and VerifyNow System [6Marcucci R. Gori A.M. Paniccia R. Giusti B. Valente S. Giglioli C. Buonamici P. Antoniucci D. Abbate R. Gensini G.F. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point‐of‐care assay: a 12‐month follow‐up.Circulation. 2009; 119: 237-42Crossref PubMed Scopus (0) Google Scholar]. For the PFA‐100 system, blood was aspirated through a capillary onto a membrane coated with collagen and either ADP (CADP) or epinephrine (CEPI) [5Campo G. Valgimigli M. Frangione A. Tebaldi M. Ferrari R. Prognostic value of serial platelet reactivity measurements on long‐term clinical outcome in patients with ST‐elevation myocardial infarction undergoing primary PCI.J Thromb Haemost. 2008; 6: 1824-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Platelet responsiveness is reported as the closure time (seconds, CADP‐CT or CEPI‐CT) needed to form a platelet plug and occlude the membrane. A patient was defined an aspirin poor responder if CEPI‐CT was < 203 [5Campo G. Valgimigli M. Frangione A. Tebaldi M. Ferrari R. Prognostic value of serial platelet reactivity measurements on long‐term clinical outcome in patients with ST‐elevation myocardial infarction undergoing primary PCI.J Thromb Haemost. 2008; 6: 1824-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The VerifyNow instrument is a turbidometric optical detection system that measures platelet‐induced aggregation as an increase in light transmittance [6Marcucci R. Gori A.M. Paniccia R. Giusti B. Valente S. Giglioli C. Buonamici P. Antoniucci D. Abbate R. Gensini G.F. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point‐of‐care assay: a 12‐month follow‐up.Circulation. 2009; 119: 237-42Crossref PubMed Scopus (0) Google Scholar]. Specific assays to test aspirin (VerifyNow Aspirin; Accumetrics Inc., San Diego, CA, USA) and clopidogrel (VerifyNow P2Y12; Accumetrics Inc.) are available. In the VerifyNow Aspirin assay, results are expressed as aspirin reaction units (ARU). Patients with ARU > 550 were considered to be aspirin poor responders. The VerifyNow P2Y12 assay was used to evaluate the clopidogrel effect on the P2Y12 receptor. The results are expressed in P2Y12 reaction units (PRU). The cut‐off value for the identification of patients with high residual platelet reactivity during clopidogrel therapy was 240 PRU [6Marcucci R. Gori A.M. Paniccia R. Giusti B. Valente S. Giglioli C. Buonamici P. Antoniucci D. Abbate R. Gensini G.F. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point‐of‐care assay: a 12‐month follow‐up.Circulation. 2009; 119: 237-42Crossref PubMed Scopus (0) Google Scholar]. The clinical endpoints were death, stroke, transient ischemic attack, myocardial infarction (MI), stent thrombosis, or rePCI [target vessel revascularization (TVR) or not]. This study was approved by the local Ethics Committee, and all patients gave written informed consent. Continuous data are presented as means ± standard deviation, and categorical variables as percentages. Statistical analyses were performed using statistica 8 (Statsoft Inc., Tulsa, OK, USA). Table 1 reports the baseline and procedural characteristics of the study population. Before admission, all patients were treated with aspirin. Three patients were admitted with ST‐segment elevation MI, and seven with non‐ST‐segment elevation acute coronary syndromes; the remainder were stable patients. This pattern of clinical presentation is similar to that observed in other PCI populations [7Marzocchi A. Saia F. Piovaccari G. Manari A. Aurier E. Benassi A. Cremonesi A. Percoco G. Varani E. Magnavacchi P. Guastaroba P. Grilli R. Maresta A. Long‐term safety and efficacy of drug‐eluting stents: two‐year results of the REAL multicenter registry.Circulation. 2007; 115: 3181-8Crossref PubMed Scopus (0) Google Scholar]. Fifteen (88%) of the 17 patients showed significant coronary artery disease that required PCI. Six (40%) patients received bare metal stents (BMSs) (eight stents for seven lesions), whereas nine (60%) received drug‐eluting stents (DESs) (13 stents for 11 lesions) (Table 1). One patient showed three‐vessel disease, and a coronary artery bypass graft was planned, and one patient showed a chronic total occlusion of the right coronary artery, and PCI was not attempted (indication for medical therapy). Aspirin (100 mg per day) was given to all patients indefinitely, whereas clopidogrel (75 mg per day) was given for 12 months to patients treated with PCI.Table 1Characteristics of the patientsCharacteristicsAll (n = 17)PCI with BMS (n = 6)PCI with DES (n = 9)Age (years)73 ± 1075 ± 1172 ± 12Men, no. (%)12 (71)4 (67)6 (67)Diabetes mellitus, no. (%)6 (35)2 (33)4 (44)Hypertension, no. (%)11 (65)5 (83)5 (55)Current smoker, no.(%)2 (12)1 (17)1 (11)Hypercholesterolemia, no. (%)7 (41)2 (33)4 (44)Medical historyCABG, no. (%)1 (6)0 (0)1 (11)PCI, no. (%)3 (18)1 (17)2 (22)MI, no. (%)2 (12)1 (17)1 (14)Clinical presentationSilent ischemia/stable angina, no. (%)7 (41)2 (33)3 (33)NSTEACS, no. (%)7 (41)3 (50)4 (44)STEMI, no. (%)3 (18)1 (17)2 (22)Killip class at entry ≥ 2, no. (%)2 (12)1 (17)1 (11)Angiographic dataMultivessel disease, no. (%)10 (58)4 (67)5 (55)Indication for PCI, no. (%)15 (88)––Target vessel of PCILeft anterior descending artery, no. (%)8 (47)3 (50)5 (55)Right coronary artery, no. (%)5 (29)2 (33)3 (33)Circumflex artery, no. (%)5 (29)2 (33)3 (33)Use of glycoprotein IIb/IIIa, no. (%)6 (35)2 (33)4 (44)Nominal stent diameter (mm)2.9 ± 0.53 ± 0.62.9 ± 0.6Total stent length (mm)31 ± 1127 ± 1533 ± 14Laboratory dataPlatelets (U/mm3)581 ± 96567 ± 101585 ± 98CEPI‐CT (s)*258 ± 51260 ± 55254 ± 60CADP‐CT (s)*115 ± 15116 ± 18115 ± 17VerifyNow Aspirin ARU*458 ± 63456 ± 65459 ± 66VerifyNow P2Y12 PRU*140 ± 47138 ± 50141 ± 49Adverse eventsFollow‐up (months)22 ± 1323 ± 1321 ± 14Death, no.000Stroke/TIA, no.000Reinfarction, no.211Stent thrombosis, no.110rePCI TVR, no.220rePCI non‐TVR, no.110BMS, bare metal stent; DES, drug eluting stent; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; MI, myocardial infarction; NSTEACS, non‐ST‐segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction; CEPI‐CT, Platelet Function Analyzer 100 collagen–epinephrine closure time; CADP‐CT, Platelet Function Analyzer 100 collagen–ADP closure time; ARU, aspirin resistance unit; PRU, P2Y12 reactivity unit; TIA, transient ischemic attack; TVR, target vessel revascularization. *Data available for 15 patients (one treated with medical therapy, six BMS group, eight DES group). Open table in a new tab BMS, bare metal stent; DES, drug eluting stent; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; MI, myocardial infarction; NSTEACS, non‐ST‐segment elevation acute coronary syndrome; STEMI, ST‐segment elevation myocardial infarction; CEPI‐CT, Platelet Function Analyzer 100 collagen–epinephrine closure time; CADP‐CT, Platelet Function Analyzer 100 collagen–ADP closure time; ARU, aspirin resistance unit; PRU, P2Y12 reactivity unit; TIA, transient ischemic attack; TVR, target vessel revascularization. *Data available for 15 patients (one treated with medical therapy, six BMS group, eight DES group). As reported in Table 1, we observed two reinfarctions and two TVR procedures (follow‐up, 22 ± 13 months; range, 6–32 months). All events occurred in patients undergoing PCI. No deaths were recorded. One reinfarction occurred for stent thrombosis and required urgent rePCI and TVR (BMS group, 5 months after index PCI, during dual antiplatelet treatment). The other one occurred in a patient of the DES group; CAA was repeated, and showed disease of a small side branch (1.5 mm). PCI was not repeated. During hospitalization, no serious bleeding events were recorded. After discharge, only one patient (DES group) stopped clopidogrel after 6 months, owing to recurrent epistaxis and ecchymosis. No other major or minor bleeding events were observed. Two of the 17 patients refused to provide the blood sample for assessment of their responses to aspirin and clopidogrel (Table 1). CEPI‐CT and CADP‐CT are shown in Table 1. With the PFA‐100, four (26%) patients were found to be aspirin poor responders. Two patients (13%) were poor responders to aspirin according to VerifyNow Aspirin. PRU values are reported in Table 1. Three (20%) patients showed residual high platelet reactivity, despite treatment with clopidogrel. It is of note that the patient with recurrence of stent thrombosis showed a poor response to aspirin (ARU = 600) and to clopidogrel (PRU = 287, percentage of inhibition = 4). The patient who prematurely stopped clopidogrel therapy had ARU = 400, PRU = 98, and percentage of inhibition by clopidogrel = 73. ET is an uncommon disease of unknown aetiology that is manifested clinically by the overproduction of platelets [1Briere J.B. Essential thrombocythemia.Orphanet J Rare Dis. 2007; 2: 3-20Crossref PubMed Scopus (81) Google Scholar]. The increased number of functionally altered thrombocytes leads to thromboembolic complications in the arterial and venous system as well as platelet‐mediated microvascular disturbances. At the same time, some patients may present with bleeding symptoms, especially those with very high platelet counts. About 10–15 cases of ET with MI have been reported [2Ozben B. Ekmekci A. Bugra Z. Umman S. Meric M. Multiple coronary thrombosis and stent implantation to the subtotally occluded right renal artery in a patient with essential thrombocytosis: a case report with review.J Thromb Thrombolysis. 2006; 22: 79-84Crossref PubMed Scopus (25) Google Scholar, 3Doesch C. Krämer B. Geisler T. May A.E. Kroeber S.M. Kandolf R. Gawaz M. Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome.J Thromb Thrombolysis. 2008; 25: 193-7Crossref PubMed Scopus (8) Google Scholar, 4Prieto R. Mart?nez‐Sellés M. Fernández‐Avilés F. Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events.Acute Card Care. 2008; 10: 116-20Crossref PubMed Scopus (0) Google Scholar], and it is commonly believed that, in this subset of patients, PCI and stent implantation may be associated with a higher rate of complications and adverse events. For the first time, we collected prospectively over 4 years the baseline data and the long‐term clinical follow‐up data of 17 patients with ET undergoing CAA (15 of 17 treated with PCI and stent implantation). The main findings of our investigation can be summarized as follows: (i) in patients with ET, the PCI procedure in combination with DES implantation appears to be effective and safe; (ii) prolonged dual antiplatelet therapy did not increase the risk of bleeding complications; and (iii) responsiveness to antiplatelet treatment is similar to that of cardiovascular patients. Despite major improvements in medical and interventional management, thrombotic events remain the primary cause of death after PCI. Although stent thrombosis is rare, the catastrophic complications lead to death in ∼ 40% of patients, and to non‐fatal MI in the majority of the others. Our data did not reveal a higher risk of thrombotic complications in patients with ET receiving PCI. Also, DES implantation is safe, with no increase in the risk of late ST. Moreover, the prolongation of dual antiplatelet therapy after DES implantation is not associated with increased bleeding complications, confirming the feasibility and safety of PCI. It has been reported that ET patients exhibit a worse response to standardized antiplatelet therapy (e.g. aspirin 100 mg per day and clopidogrel 75 mg per day) [3Doesch C. Krämer B. Geisler T. May A.E. Kroeber S.M. Kandolf R. Gawaz M. Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome.J Thromb Thrombolysis. 2008; 25: 193-7Crossref PubMed Scopus (8) Google Scholar]. Our data showed that in patients with ET who were carefully managed for their hematologic disorder, the responsiveness to aspirin and clopidogrel did not differ from that observed in cardiovascular disease patients treated with PCI [4Prieto R. Mart?nez‐Sellés M. Fernández‐Avilés F. Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events.Acute Card Care. 2008; 10: 116-20Crossref PubMed Scopus (0) Google Scholar, 5Campo G. Valgimigli M. Frangione A. Tebaldi M. Ferrari R. Prognostic value of serial platelet reactivity measurements on long‐term clinical outcome in patients with ST‐elevation myocardial infarction undergoing primary PCI.J Thromb Haemost. 2008; 6: 1824-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Marcucci R. Gori A.M. Paniccia R. Giusti B. Valente S. Giglioli C. Buonamici P. Antoniucci D. Abbate R. Gensini G.F. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point‐of‐care assay: a 12‐month follow‐up.Circulation. 2009; 119: 237-42Crossref PubMed Scopus (0) Google Scholar, 7Marzocchi A. Saia F. Piovaccari G. Manari A. Aurier E. Benassi A. Cremonesi A. Percoco G. Varani E. Magnavacchi P. Guastaroba P. Grilli R. Maresta A. Long‐term safety and efficacy of drug‐eluting stents: two‐year results of the REAL multicenter registry.Circulation. 2007; 115: 3181-8Crossref PubMed Scopus (0) Google Scholar, 8Campo G. Valgimigli M. Gemmati D. Percoco G. Catozzi L. Frangione A. Federici F. Ferrari F. Tebaldi M. Luccarelli S. Parrinello G. Ferrari R. Poor responsiveness to clopidogrel: drug‐specific or class‐effect mechanism? Evidence from a clopidogrel‐to‐ticlopidine crossover study.J Am Coll Cardiol. 2007; 50: 1132-7Crossref PubMed Scopus (0) Google Scholar]. We found that ∼ 20% of patients exhibited a poor response, which is consistent with previous studies in patients with coronary artery disease undergoing PCI and with normal platelet counts [5Campo G. Valgimigli M. Frangione A. Tebaldi M. Ferrari R. Prognostic value of serial platelet reactivity measurements on long‐term clinical outcome in patients with ST‐elevation myocardial infarction undergoing primary PCI.J Thromb Haemost. 2008; 6: 1824-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 6Marcucci R. Gori A.M. Paniccia R. Giusti B. Valente S. Giglioli C. Buonamici P. Antoniucci D. Abbate R. Gensini G.F. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point‐of‐care assay: a 12‐month follow‐up.Circulation. 2009; 119: 237-42Crossref PubMed Scopus (0) Google Scholar, 7Marzocchi A. Saia F. Piovaccari G. Manari A. Aurier E. Benassi A. Cremonesi A. Percoco G. Varani E. Magnavacchi P. Guastaroba P. Grilli R. Maresta A. Long‐term safety and efficacy of drug‐eluting stents: two‐year results of the REAL multicenter registry.Circulation. 2007; 115: 3181-8Crossref PubMed Scopus (0) Google Scholar, 8Campo G. Valgimigli M. Gemmati D. Percoco G. Catozzi L. Frangione A. Federici F. Ferrari F. Tebaldi M. Luccarelli S. Parrinello G. Ferrari R. Poor responsiveness to clopidogrel: drug‐specific or class‐effect mechanism? Evidence from a clopidogrel‐to‐ticlopidine crossover study.J Am Coll Cardiol. 2007; 50: 1132-7Crossref PubMed Scopus (0) Google Scholar, 9Angiolillo D.J. Shoemaker S.B. Desai B. Yuan H. Charlton R.K. Bernardo E. Zenni M.M. Guzman L.A. Bass T.A. Costa M.A. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.Circulation. 2007; 115: 708-16Crossref PubMed Scopus (437) Google Scholar]. Nevertheless, we believe that antiplatelet therapy monitoring using point‐of‐care tests may be helpful in this subset of patients. In our study group, only one serious adverse event was observed (stent thrombosis 5 months after index PCI, leading to reinfarction and rePCI). This patient showed poor responses to both aspirin and clopidogrel. In previous studies, the adjustment of clopidogrel therapy has been effective in reducing the platelet reactivity and the rate of ischemic complications [9Angiolillo D.J. Shoemaker S.B. Desai B. Yuan H. Charlton R.K. Bernardo E. Zenni M.M. Guzman L.A. Bass T.A. Costa M.A. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.Circulation. 2007; 115: 708-16Crossref PubMed Scopus (437) Google Scholar, 10Bonello L. Camoin‐Jau L. Arques S. Boyer C. Panagides D. Wittenberg O. Simeoni M.C. Barragan P. Dignat‐George F. Paganelli F. Adjusted clopidogrel loading doses according to vasodilator‐stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study.J Am Coll Cardiol. 2008; 51: 1404-11Crossref PubMed Scopus (0) Google Scholar]. It is therefore plausible that ET patients who are poor responders to oral antiplatelet treatment could obtain an important clinical benefit from an individual dose adjustment by point‐of‐care testing. Moreover, a tailored approach towards the antiplatelet therapy based on serial measurements may also minimize bleeding complications. In conclusion, our data do not show an increased risk of adverse events in ET patients treated with PCI, stent implantation, and prolonged dual antiplatelet therapy. The authors state that they have no conflict of interest. The authors thank M. Monti and S. Gambetti (Medical Trials Analysis, Italy) for their assistance in the collection of data and platelet function tests.
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