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Effectiveness and Safety of the Genous Endothelial Progenitor Cell-Capture Stent in Acute ST-Elevation Myocardial Infarction
Effectiveness and Safety of the Genous Endothelial Progenitor Cell-Capture Stent in Acute ST-Elevation Myocardial Infarction Adrian F. Low, MBBS*, Chi-Hang Lee, MD, Swee-Guan Teo, MBBS, Mark Y. Chan, MBBS, Edgar Tay, MBBS, Yian-Ping Lee, MBBS, Eric Chong, MBBS, Melissa Co, MD, Eduardo Tin Hay, MD, Yean-Teng Lim, MBBS, and Huay-Cheem Tan, MBBS The endothelial progenitor cell (EPC)-capture stent promotes endothelialization and preliminary studies have suggested its safety and feasibility in ST-elevation myocardial infarction (STEMI). Detailed late clinical follow-up and angiographic analyses are, however, limited. We sought to determine late angiographic and clinical outcomes of the Genous EPC-capture stent in primary angioplasty. EPC-capture stents were implanted during primary angioplasty in 489 consecutive patients presenting with STEMI from 2004 through 2008. The first 100 consenting patients undergoing successful stent implantation scheduled to undergo relook coronary angiography at 6 to 12 months were enrolled. Ninety-five patients with 96 lesions were analyzed independently. Mean duration of follow-up coronary angiography was 245 days. In-stent late luminal loss measured 0.87 ⴞ 0.67 mm. Binary restenosis (defined as >50% diameter stenosis) was 28%, with diffuse in-stent restenosis (Mehran class II) as the predominant pattern. Of 27 patients with binary restenosis, 14 (52%) were symptomatic, with 10 patients undergoing target lesion revascularization. Asymptomatic patients had significantly larger reference vessel and in-stent minimal luminal diameters (2.77 ⴞ 0.39 vs 2.54 ⴞ 0.44 mm, p ⴝ 0.040; 2.74 ⴞ 0.34 vs 2.31 ⴞ 0.72 mm, p ⴝ 0.004, respectively). Follow-up late loss and diameter stenoses were also in favor of the asymptomatic group. Major adverse cardiac event rate was 16% at a mean follow-up of 34 months. There were no cases of Academic Research Consortium– defined stent thrombosis. In conclusion, implantation of the EPC-capture stent during primary angioplasty is associated with a favorable late clinical outcome but with higher than anticipated angiographic late loss. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:202–205) In our institution, the Genous endothelial progenitor cell (EPC)-capture stent has been used routinely in patients with ST-elevation myocardial infarction (STEMI) without cardiogenic shock since 2004. We have published data supporting its utility in this setting.1–3 Other investigators have similarly substantiated its safety in this and other high-risk settings.4 – 6 Although clinical outcome has been favorable, this has been restricted to relatively short-term follow-up. There is a paucity of data on its late loss, an angiographic index that has been proposed to be a more efficient estimate of in-stent restenosis in this era of low binary restenosis rates.7 To compare its long-term restenosis rate with drugeluting stents, angiographic data and in particular late loss measurements are necessary. We evaluated angiographic findings and long-term clinical outcomes of patients with STEMI treated with the Genous EPC-capture stent.
National University Heart Centre, Singapore. The study was sponsored largely by the institution, Singapore. The independent angiographic core laboratory adjudication was funded by OrbusNeich, Wanchai, Hong Kong. *Corresponding author: Tel: 65-6772-5211; fax: 65-6872-2998. E-mail address: [email protected] (A.F. Low). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.03.024
Methods At our institution, all patients undergoing primary angioplasty for STEMI but no cardiogenic shock have been treated with the Genous EPC-capture stent (OrbusNeich, Wanchai, Hong Kong) since late 2004. Primary angioplasty was performed according to standard practice. The detailed interventional strategy was left to the discretion of the individual operator. Weight-adjusted heparin was administered to achieve an activated clotting time ⬎300 seconds or 200 to 250 seconds when platelet glycoprotein IIb/IIIa inhibitors were used. After stent implantation, patients were prescribed lifelong aspirin (100 mg/day) and clopidogrel (75 mg daily) for 1 month. The local ethics committee approved the study protocol and informed consent was obtained from all patients. From June 2004 through April 2008, 489 patients with STEMI received this stent and were followed up clinically. Angiographic follow-up at 6 to 12 months was proposed for these patients and our intent was to analyze follow-up angiographic findings of the first 100 consenting patients from this cohort. Symptomatic and asymptomatic patients were considered. Angiographic follow-up and clinical adjudication were conducted in blinded fashion by an independent core laboratory (Cardiovascular Research Foundation, New York, New York). Quantitative coronary angiography was perwww.ajconline.org
Coronary Artery Disease/Use of EPC-Capture Stent in STEMI Table 1 Clinical characteristics of 95 patients with ST-segment elevation myocardial infarction and follow-up coronary angiography at six to 12 months Age (years), mean ⫾ SD Men Diabetes mellitus Hypertension Hypercholesterolemia* Smoker Family history of premature coronary heart disease Coronary artery involved Left anterior descending artery coronary artery Left circumflex artery Right coronary artery Left main coronary artery
54 ⫾ 10 94% 29% 50% 76% 65% 7.3% 58% 6% 35% 1%
* Defined as previous use of a statin drug, total cholesterol level ⱖ6.2 mmol/L, or low-density lipoprotein level ⱖ3.4 mmol/L.
Table 2 Coronary angiographic findings at baseline, immediately after procedure, and at follow-up Before primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) Diameter stenosis (%) Immediately after primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) Follow-up coronary angiography Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Late luminal loss (mm) In stent In segment Diameter stenosis (%) Binary restenosis ⬎50% diameter stenosis (%)
2.68 ⫾ 0.52 0.14 ⫾ 0.27 95 ⫾ 9 2.73 ⫾ 0.41 2.66 ⫾ 0.46 2.28 ⫾ 0.45 17 ⫾ 12 2.87 ⫾ 0.38 1.79 ⫾ 0.71 1.71 ⫾ 0.67 0.87 ⫾ 0.67 0.56 ⫾ 0.62 39 ⫾ 22 28
formed in the standard fashion and binary restenosis was defined as ⬎50% diameter stenosis. Patients were followed clinically until February 2010 for the development of major adverse cardiac events (MACEs), defined as repeat target vessel revascularization, acute MI, and cardiac death. Statistical analysis was performed using STATA 9.2 (STATA Corporation, College Station, Texas). Discrete data were presented as frequencies and/or percentages and continuous variables were presented as means ⫾ SDs. Mann–Whitney 2-sample Wilcoxon rank-sum test was used to compare angiographic measurements between symptomatic and asymptomatic patients. A p value ⬍0.05 was used to indicate statistical significance. Results Ninety-five patients with 96 lesions were subsequently analyzed. Although we had intended 100 patients, 5 patients were excluded because their follow-up coronary angiograms were
203
Table 3 In-stent restenosis pattern in 27 patients with binary restenosis (⬎50% diameter stenosis) on follow-up coronary angiogram Focal margin in-stent restenosis (Mehran class IB) Focal body in-stent restenosis (Mehran class IC) Diffuse in-stent restenosis (Mehran class II) Proliferative in-stent restenosis (Mehran class III) Total occlusion in-stent restenosis (Mehran class IV)
4 (15%) 1 (4%) 17 (62%) 4 (15%) 1 (4%)
outside the prespecified stipulated window period of 6 to 12 months. Mean duration of follow-up coronary angiography was 245 ⫾ 62 days. Clinical characteristics of these 95 patients are presented in Table 1. Glycoprotein IIb/IIIa inhibitors were used in 29 patients (30%). Fifty-three patients (56%) underwent balloon dilation before stent implantation. Similarly, 53 patients underwent thrombus aspiration alone as a prelude to stenting. Twenty-eight patients (29%) had thrombus aspiration and balloon dilation before stent implant. Average stent diameter and stent segment length were 2.96 ⫾ 0.33 and 23.00 ⫾ 9.58 mm, respectively. Eighty-eight patients required just 1 stent, whereas 2 patients required implantation of 3 overlapping Genous stents for a diffuse lesion. Four patients required 2 overlapping stents for diffuse lesions and 1 patient required 2 stents at 2 discrete stenoses of the culprit artery. Coronary angiographic findings at presentation are presented in Table 2. After primary angioplasty, 86 patients (91%) had restored Thrombolysis In Myocardial Infarction grade 3 flow, 8 patients (8%) had grade 2 flow, and only 1 patients (1%) had grade 0 flow after the procedure. Cardiac echocardiography performed after the intervention showed a median left ventricular ejection fraction of 47% (interquartile range 18) in the cohort. Median peak creatine kinase measured 2,754 U/L (interquartile range 3,012), and 82% of patients had complete resolution of ST-segment elevation after the intervention. At follow-up coronary angiography, mean diameter stenosis measured 39% and in-stent late luminal loss measured 0.87 ⫾ 0.67 mm (Table 2). In-stent restenosis patterns in 27 patients with binary restenosis are presented in Table 3. Because symptomatic patients were more inclined to undergo relook coronary angiography, we also considered angiographic findings when these patients were excluded. Of 95 patients evaluated, 79 (82%) were asymptomatic. Repeat analysis of these 79 asymptomatic patients showed similar findings (Table 4). We then investigated whether there were significant differences between symptomatic and asymptomatic patients with regard to measured angiographic parameters. There were no differences in preprocedure parameters. However, asymptomatic patients had significantly larger reference vessel and in-stent minimal luminal diameters at the index procedure (Table 4). Follow-up minimal luminal diameters, late loss, and diameter stenoses were also in favor of the asymptomatic group. Considering clinical outcomes, mean duration follow-up was 34 months. MACEs occurred in 15 patients. Two patients presented with an acute MI; 1 was clearly unrelated to the culprit vessel at the index event and the other patient
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Table 4 Coronary angiographic findings at baseline, immediately after procedure, and at follow-up in asymptomatic patients (n ⫽ 79) p Value Before primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) Diameter stenosis (%) Immediately after primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) Follow-up coronary angiography Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Late luminal loss (mm) In stent In segment Diameter stenosis (%) Binary restenosis ⬎50% diameter stenosis (%) Angiographic parameters different from symptomatic patients Postangioplasty reference vessel diameter (mm) Postangioplasty in-stent minimal luminal diameter (mm) Follow-up in-stent minimal luminal diameter (mm) Follow-up in-segment minimal luminal diameter (mm) Follow-up in-stent late loss (mm) Follow-up in-segment late loss (mm) Follow-up diameter stenosis (%)
2.69 ⫾ 0.54 0.13 ⫾ 0.25 95 ⫾ 9 2.77 ⫾ 0.39 2.74 ⫾ 0.34 2.32 ⫾ 0.38 16 ⫾ 8 2.87 ⫾ 0.38 1.93 ⫾ 0.65 1.86 ⫾ 0.60 0.81 ⫾ 0.60 0.46 ⫾ 0.54 33 ⫾ 18 16 2.77 ⫾ 0.39 vs 2.54 ⫾ 0.44 2.74 ⫾ 0.34 vs 2.31 ⫾ 0.72 1.93 ⫾ 0.65 vs 1.17 ⫾ 0.63 1.86 ⫾ 0.60 vs 1.05 ⫾ 0.59 0.81 ⫾ 0.60 vs 1.14 ⫾ 0.92 0.46 ⫾ 0.54 vs 1.01 ⫾ 0.78 33 ⫾ 18 vs 64 ⫾ 19
0.040 0.004 ⬍0.001 ⬍0.001 0.021 ⬍0.001 ⬍0.001
event rate was 16% and event-free survival is depicted in Figure 1. Discussion
Figure 1. Kaplan–Meier event-free survival estimate of the patient cohort with follow-up to 34 months. Major adverse cardiac events were defined as repeat target vessel revascularization, acute myocardial infarction, and cardiac death.
developed a non-STEMI with clear disease progression of all 3 coronary vessels. No cases of Academic Research Consortium– defined stent thrombosis were observed. There were no cardiac-related deaths during the period of study and the remaining 13 events were attributed to in-stent restenosis. Nine of these 13 patients were symptomatic. Four patients underwent coronary artery bypass surgery and the remaining 5 patients were treated percutaneously. Total
To our knowledge, this is the largest published study systematically evaluating angiographic outcome in patients treated with the Genous EPC-capture stent in the STEMI setting. Our results also complement the current literature on clinical outcome.1– 6,8,9 Taken together, these data suggest that the Genous EPC-capture stent is a safe choice in patients presenting with STEMI. In-stent restenosis, however, does not appear comparable to drug-eluting stents. A previous study of 10 patients in the acute MI setting suggested a late luminal loss at 8 months of 0.97 ⫾ 0.94 mm and a binary restenosis rate of 50%, although repeat revascularization was only 10%.10 Despite a binary restenosis rate of 28%, MACEs were only 16% at a mean follow-up of 34 months. This may be consequent to the absence of symptoms in an infarcted territory. In addition, angiographic stenosis not uncommonly overestimates functional severity.11 Currently available data on late luminal loss with use of the Genous EPC-capture stent in a variety of settings have documented a late loss of 0.63 to 1.14 mm.4,8,12,13 Our findings are consistent with these published data and suggest a similar late luminal loss to that of a bare-metal stent. Despite initial optimism that rapid endothelialization might favor late luminal loss, this has not been borne out in studies.
Coronary Artery Disease/Use of EPC-Capture Stent in STEMI
A recent meta-analysis has suggested benefits with routine use of drug-eluting stents in STEMI.14 Others, however, have cautioned against its routine use in this setting.15,16 No cases of late stent thrombosis were observed in our patient cohort and we are aware of only 1 incident of late stent thrombosis associated with the Genous EPC-capture stent.17 In this patient, intravascular ultrasound documented an undersized stent with malapposition. This strategy of using covalently bonded monoclonal antibodies to capture circulating stem cells and promote endothelialization appears contrary to drug-eluting stents, which inhibit cellular proliferation with an antiproliferative agent. This has resulted in a hypothesis suggesting a combined approach where the theoretical benefit of increased endothelialization is supplemented with an antiproliferative drug to address the increased late loss. A novel stent platform has been developed with an EPC-coating on the luminal aspect and the addition of sirolimus on the abluminal surface. A Prospective, Randomized Study to Evaluate the Safety and Effectiveness of an AbluMinal Sirolimus CoatED Bio-Engineered StEnt (Combo Bio- Engineered Sirolimus Eluting Stent) Compared with a TAXUS Liberté Stent Control Arm for Treatment of Stenotic Lesions in Native Coronary Arteries (REMEDEE) study is currently ongoing to evaluate this novel combination stent and preliminary results are anticipated in late 2011. 1. Lee YP, Tay E, Lee CH, Low A, Teo SG, Poh KK, Yeo WT, Lim J, Lim IH, Lim YT, Tan HC. Endothelial progenitor cell capture stent implantation in patients with ST-segment elevation acute myocardial infarction: one year follow-up. Eurointervention 2010;5:698 –702. 2. Chong E, Poh KK, Liang S, Lee RC, Low A, Teo SG, Tan HC. Two-year clinical registry follow-up of endothelial progenitor cell capture stent versus sirolimus-eluting bioabsorbable polymer-coated stent versus bare metal stents in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction. J Interv Cardiol 2010;23:101–108. 3. Co M, Tay E, Lee CH, Poh KK, Low A, Lim J, Lim IH, Lim YT, Tan HC. Use of endothelial progenitor cell capture stent (Genous BioEngineered R Stent) during primary percutaneous coronary intervention in acute myocardial infarction: Intermediate- to long-term clinical follow-up. Am Heart J 2008;155:128 –132. 4. Miglionico M, Patti G, D’Ambrosio A, Di Sciascio G. Percutaneous coronary intervention utilizing a new endothelial progenitor cells antibody-coated stent: a prospective single-center registry in high-risk patients. Catheter Cardiovasc Interv 2008;71:600 – 604. 5. Jim MH, Yung AS, Tang GK, Fan KY, Chow WH. Successful use of endothelial progenitor cell capture stents in a coronary artery disease patient with aspirin hypersensitivity who failed initial aspirin desensitization. Int J Cardiol 2010 [Epub ahead of print]. 6. Lee WL, Ho HH, Chan KW, Hai SH, Sin WC, Tam CC, Lam L, Chan HW. Successful use of endothelial progenitor cell capture stents in two cases of acute coronary syndrome complicated by major bleeding episodes. Int J Cardiol 2011;14:224 –226.
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7. Mauri L, Orav EJ, O’Malley AJ, Moses JW, Leon MB, Holmes DR, Teirstein PS, Schofer J, Breithardt G, Cutlip DE, Kereiakes DJ, Shi C, Firth BG, Donohoe DJ, Kuntz RE. Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents. Circulation 2005;111:321–327. 8. Aoki J, Serruys PW, van Beusekom H, Ong AT, McFadden EP, Sianos G, van der Giessen WJ, Regar E, de Feyter PJ, Davis HR, Rowland S, Kutryk MJ. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 2005;45:1574 –1579. 9. Duckers HJ, Soullié T, den Heijer P, Rensing B, de Winter RJ, Rau M, Mudra H, Silber S, Benit E, Verheye S, Wijns W, Serruys PW. Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent). Eurointervention 2007;3:350 –358. 10. Kaul U, Bhatia V, Ghose T, Gupta R, Kachru R, Singh G. Angiographic follow-up of Genous Bioengineered Stent in Acute Myocardial Infarction (GENAMI)—a pilot study. Indian Heart J 2008;60:532– 535. 11. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, Maccarthy PA, Van’t Veer M, Pijls NH. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55:2816 –2821. 12. Duckers HJ, Silber S, de Winter R, den Heijer P, Rensing B, Rau M, Mudra H, Benit E, Verheye S, Wijns W, Serruys PW. Circulating endothelial progenitor cells predict angiographic and intravascular ultrasound outcome following percutaneous coronary interventions in the HEALING-II trial: evaluation of an endothelial progenitor cell capturing stent. Eurointervention 2007;3:67–75. 13. Beijk MA, Klomp M, Verouden NJ, van Geloven N, Koch KT, Henriques JP, Baan J, Vis MM, Scheunhage E, Piek JJ, Tijssen JG, de Winter RJ. Genous endothelial progenitor cell capturing stent vs. the Taxus Liberte stent in patients with de novo coronary lesions with a high-risk of coronary restenosis: a randomized, single-centre, pilot study. Eur Heart J 2010;31:1055–1064. 14. Piscione F, Piccolo R, Cassese S, Galasso G, De Rosa R, D’Andrea C, Chiariello M. Effect of drug-eluting stents in patients with acute ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: a meta-analysis of randomised trials and an adjusted indirect comparison. Eurointervention 2010;5:853– 860. 15. Kaltoft A, Kelbaek H, Thuesen L, Lassen JF, Clemmensen P, Kløvgaard L, Engstrøm T, Bøtker HE, Saunamäki K, Krusell LR, Jørgensen E, Tilsted HH, Christiansen EH, Ravkilde J, Køber L, Kofoed KF, Terkelsen CJ, Helqvist S. Long-term outcome after drug-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: 3-year follow-up of the randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) Trial. J Am Coll Cardiol 2010;56:641– 645. 16. Brodie B, Pokharel Y, Fleishman N, Bensimhon A, Kissling G, Hansen C, Milks S, Cooper M, McAlhany C, Stuckey T. Very late stent thrombosis after primary percutaneous coronary intervention with bare-metal and drug-eluting stents for ST-segment elevation myocardial infarction: a 15-year single-center experience. JACC Cardiovasc Interv 2011;4:30 –38. 17. Rossi ML, Zavalloni D, Gasparini GL, Mango R, Belli G, Presbitero P. The first report of late stent thrombosis leading to acute myocardial infarction in patient receiving the new endothelial progenitor cell capture stent. Int J Cardiol 2010;141:e20 – e22.
National University Heart Centre, Singapore. The study was sponsored largely by the institution, Singapore. The independent angiographic core laboratory adjudication was funded by OrbusNeich, Wanchai, Hong Kong. *Corresponding author: Tel: 65-6772-5211; fax: 65-6872-2998. E-mail address: [email protected] (A.F. Low). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.03.024
Methods At our institution, all patients undergoing primary angioplasty for STEMI but no cardiogenic shock have been treated with the Genous EPC-capture stent (OrbusNeich, Wanchai, Hong Kong) since late 2004. Primary angioplasty was performed according to standard practice. The detailed interventional strategy was left to the discretion of the individual operator. Weight-adjusted heparin was administered to achieve an activated clotting time ⬎300 seconds or 200 to 250 seconds when platelet glycoprotein IIb/IIIa inhibitors were used. After stent implantation, patients were prescribed lifelong aspirin (100 mg/day) and clopidogrel (75 mg daily) for 1 month. The local ethics committee approved the study protocol and informed consent was obtained from all patients. From June 2004 through April 2008, 489 patients with STEMI received this stent and were followed up clinically. Angiographic follow-up at 6 to 12 months was proposed for these patients and our intent was to analyze follow-up angiographic findings of the first 100 consenting patients from this cohort. Symptomatic and asymptomatic patients were considered. Angiographic follow-up and clinical adjudication were conducted in blinded fashion by an independent core laboratory (Cardiovascular Research Foundation, New York, New York). Quantitative coronary angiography was perwww.ajconline.org
Coronary Artery Disease/Use of EPC-Capture Stent in STEMI Table 1 Clinical characteristics of 95 patients with ST-segment elevation myocardial infarction and follow-up coronary angiography at six to 12 months Age (years), mean ⫾ SD Men Diabetes mellitus Hypertension Hypercholesterolemia* Smoker Family history of premature coronary heart disease Coronary artery involved Left anterior descending artery coronary artery Left circumflex artery Right coronary artery Left main coronary artery
54 ⫾ 10 94% 29% 50% 76% 65% 7.3% 58% 6% 35% 1%
* Defined as previous use of a statin drug, total cholesterol level ⱖ6.2 mmol/L, or low-density lipoprotein level ⱖ3.4 mmol/L.
Table 2 Coronary angiographic findings at baseline, immediately after procedure, and at follow-up Before primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) Diameter stenosis (%) Immediately after primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) Follow-up coronary angiography Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Late luminal loss (mm) In stent In segment Diameter stenosis (%) Binary restenosis ⬎50% diameter stenosis (%)
2.68 ⫾ 0.52 0.14 ⫾ 0.27 95 ⫾ 9 2.73 ⫾ 0.41 2.66 ⫾ 0.46 2.28 ⫾ 0.45 17 ⫾ 12 2.87 ⫾ 0.38 1.79 ⫾ 0.71 1.71 ⫾ 0.67 0.87 ⫾ 0.67 0.56 ⫾ 0.62 39 ⫾ 22 28
formed in the standard fashion and binary restenosis was defined as ⬎50% diameter stenosis. Patients were followed clinically until February 2010 for the development of major adverse cardiac events (MACEs), defined as repeat target vessel revascularization, acute MI, and cardiac death. Statistical analysis was performed using STATA 9.2 (STATA Corporation, College Station, Texas). Discrete data were presented as frequencies and/or percentages and continuous variables were presented as means ⫾ SDs. Mann–Whitney 2-sample Wilcoxon rank-sum test was used to compare angiographic measurements between symptomatic and asymptomatic patients. A p value ⬍0.05 was used to indicate statistical significance. Results Ninety-five patients with 96 lesions were subsequently analyzed. Although we had intended 100 patients, 5 patients were excluded because their follow-up coronary angiograms were
203
Table 3 In-stent restenosis pattern in 27 patients with binary restenosis (⬎50% diameter stenosis) on follow-up coronary angiogram Focal margin in-stent restenosis (Mehran class IB) Focal body in-stent restenosis (Mehran class IC) Diffuse in-stent restenosis (Mehran class II) Proliferative in-stent restenosis (Mehran class III) Total occlusion in-stent restenosis (Mehran class IV)
4 (15%) 1 (4%) 17 (62%) 4 (15%) 1 (4%)
outside the prespecified stipulated window period of 6 to 12 months. Mean duration of follow-up coronary angiography was 245 ⫾ 62 days. Clinical characteristics of these 95 patients are presented in Table 1. Glycoprotein IIb/IIIa inhibitors were used in 29 patients (30%). Fifty-three patients (56%) underwent balloon dilation before stent implantation. Similarly, 53 patients underwent thrombus aspiration alone as a prelude to stenting. Twenty-eight patients (29%) had thrombus aspiration and balloon dilation before stent implant. Average stent diameter and stent segment length were 2.96 ⫾ 0.33 and 23.00 ⫾ 9.58 mm, respectively. Eighty-eight patients required just 1 stent, whereas 2 patients required implantation of 3 overlapping Genous stents for a diffuse lesion. Four patients required 2 overlapping stents for diffuse lesions and 1 patient required 2 stents at 2 discrete stenoses of the culprit artery. Coronary angiographic findings at presentation are presented in Table 2. After primary angioplasty, 86 patients (91%) had restored Thrombolysis In Myocardial Infarction grade 3 flow, 8 patients (8%) had grade 2 flow, and only 1 patients (1%) had grade 0 flow after the procedure. Cardiac echocardiography performed after the intervention showed a median left ventricular ejection fraction of 47% (interquartile range 18) in the cohort. Median peak creatine kinase measured 2,754 U/L (interquartile range 3,012), and 82% of patients had complete resolution of ST-segment elevation after the intervention. At follow-up coronary angiography, mean diameter stenosis measured 39% and in-stent late luminal loss measured 0.87 ⫾ 0.67 mm (Table 2). In-stent restenosis patterns in 27 patients with binary restenosis are presented in Table 3. Because symptomatic patients were more inclined to undergo relook coronary angiography, we also considered angiographic findings when these patients were excluded. Of 95 patients evaluated, 79 (82%) were asymptomatic. Repeat analysis of these 79 asymptomatic patients showed similar findings (Table 4). We then investigated whether there were significant differences between symptomatic and asymptomatic patients with regard to measured angiographic parameters. There were no differences in preprocedure parameters. However, asymptomatic patients had significantly larger reference vessel and in-stent minimal luminal diameters at the index procedure (Table 4). Follow-up minimal luminal diameters, late loss, and diameter stenoses were also in favor of the asymptomatic group. Considering clinical outcomes, mean duration follow-up was 34 months. MACEs occurred in 15 patients. Two patients presented with an acute MI; 1 was clearly unrelated to the culprit vessel at the index event and the other patient
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Table 4 Coronary angiographic findings at baseline, immediately after procedure, and at follow-up in asymptomatic patients (n ⫽ 79) p Value Before primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) Diameter stenosis (%) Immediately after primary angioplasty Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Diameter stenosis (%) Follow-up coronary angiography Diameter of reference vessel (mm) Minimal luminal diameter (mm) In stent In segment Late luminal loss (mm) In stent In segment Diameter stenosis (%) Binary restenosis ⬎50% diameter stenosis (%) Angiographic parameters different from symptomatic patients Postangioplasty reference vessel diameter (mm) Postangioplasty in-stent minimal luminal diameter (mm) Follow-up in-stent minimal luminal diameter (mm) Follow-up in-segment minimal luminal diameter (mm) Follow-up in-stent late loss (mm) Follow-up in-segment late loss (mm) Follow-up diameter stenosis (%)
2.69 ⫾ 0.54 0.13 ⫾ 0.25 95 ⫾ 9 2.77 ⫾ 0.39 2.74 ⫾ 0.34 2.32 ⫾ 0.38 16 ⫾ 8 2.87 ⫾ 0.38 1.93 ⫾ 0.65 1.86 ⫾ 0.60 0.81 ⫾ 0.60 0.46 ⫾ 0.54 33 ⫾ 18 16 2.77 ⫾ 0.39 vs 2.54 ⫾ 0.44 2.74 ⫾ 0.34 vs 2.31 ⫾ 0.72 1.93 ⫾ 0.65 vs 1.17 ⫾ 0.63 1.86 ⫾ 0.60 vs 1.05 ⫾ 0.59 0.81 ⫾ 0.60 vs 1.14 ⫾ 0.92 0.46 ⫾ 0.54 vs 1.01 ⫾ 0.78 33 ⫾ 18 vs 64 ⫾ 19
0.040 0.004 ⬍0.001 ⬍0.001 0.021 ⬍0.001 ⬍0.001
event rate was 16% and event-free survival is depicted in Figure 1. Discussion
Figure 1. Kaplan–Meier event-free survival estimate of the patient cohort with follow-up to 34 months. Major adverse cardiac events were defined as repeat target vessel revascularization, acute myocardial infarction, and cardiac death.
developed a non-STEMI with clear disease progression of all 3 coronary vessels. No cases of Academic Research Consortium– defined stent thrombosis were observed. There were no cardiac-related deaths during the period of study and the remaining 13 events were attributed to in-stent restenosis. Nine of these 13 patients were symptomatic. Four patients underwent coronary artery bypass surgery and the remaining 5 patients were treated percutaneously. Total
To our knowledge, this is the largest published study systematically evaluating angiographic outcome in patients treated with the Genous EPC-capture stent in the STEMI setting. Our results also complement the current literature on clinical outcome.1– 6,8,9 Taken together, these data suggest that the Genous EPC-capture stent is a safe choice in patients presenting with STEMI. In-stent restenosis, however, does not appear comparable to drug-eluting stents. A previous study of 10 patients in the acute MI setting suggested a late luminal loss at 8 months of 0.97 ⫾ 0.94 mm and a binary restenosis rate of 50%, although repeat revascularization was only 10%.10 Despite a binary restenosis rate of 28%, MACEs were only 16% at a mean follow-up of 34 months. This may be consequent to the absence of symptoms in an infarcted territory. In addition, angiographic stenosis not uncommonly overestimates functional severity.11 Currently available data on late luminal loss with use of the Genous EPC-capture stent in a variety of settings have documented a late loss of 0.63 to 1.14 mm.4,8,12,13 Our findings are consistent with these published data and suggest a similar late luminal loss to that of a bare-metal stent. Despite initial optimism that rapid endothelialization might favor late luminal loss, this has not been borne out in studies.
Coronary Artery Disease/Use of EPC-Capture Stent in STEMI
A recent meta-analysis has suggested benefits with routine use of drug-eluting stents in STEMI.14 Others, however, have cautioned against its routine use in this setting.15,16 No cases of late stent thrombosis were observed in our patient cohort and we are aware of only 1 incident of late stent thrombosis associated with the Genous EPC-capture stent.17 In this patient, intravascular ultrasound documented an undersized stent with malapposition. This strategy of using covalently bonded monoclonal antibodies to capture circulating stem cells and promote endothelialization appears contrary to drug-eluting stents, which inhibit cellular proliferation with an antiproliferative agent. This has resulted in a hypothesis suggesting a combined approach where the theoretical benefit of increased endothelialization is supplemented with an antiproliferative drug to address the increased late loss. A novel stent platform has been developed with an EPC-coating on the luminal aspect and the addition of sirolimus on the abluminal surface. A Prospective, Randomized Study to Evaluate the Safety and Effectiveness of an AbluMinal Sirolimus CoatED Bio-Engineered StEnt (Combo Bio- Engineered Sirolimus Eluting Stent) Compared with a TAXUS Liberté Stent Control Arm for Treatment of Stenotic Lesions in Native Coronary Arteries (REMEDEE) study is currently ongoing to evaluate this novel combination stent and preliminary results are anticipated in late 2011. 1. Lee YP, Tay E, Lee CH, Low A, Teo SG, Poh KK, Yeo WT, Lim J, Lim IH, Lim YT, Tan HC. Endothelial progenitor cell capture stent implantation in patients with ST-segment elevation acute myocardial infarction: one year follow-up. Eurointervention 2010;5:698 –702. 2. Chong E, Poh KK, Liang S, Lee RC, Low A, Teo SG, Tan HC. Two-year clinical registry follow-up of endothelial progenitor cell capture stent versus sirolimus-eluting bioabsorbable polymer-coated stent versus bare metal stents in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction. J Interv Cardiol 2010;23:101–108. 3. Co M, Tay E, Lee CH, Poh KK, Low A, Lim J, Lim IH, Lim YT, Tan HC. Use of endothelial progenitor cell capture stent (Genous BioEngineered R Stent) during primary percutaneous coronary intervention in acute myocardial infarction: Intermediate- to long-term clinical follow-up. Am Heart J 2008;155:128 –132. 4. Miglionico M, Patti G, D’Ambrosio A, Di Sciascio G. Percutaneous coronary intervention utilizing a new endothelial progenitor cells antibody-coated stent: a prospective single-center registry in high-risk patients. Catheter Cardiovasc Interv 2008;71:600 – 604. 5. Jim MH, Yung AS, Tang GK, Fan KY, Chow WH. Successful use of endothelial progenitor cell capture stents in a coronary artery disease patient with aspirin hypersensitivity who failed initial aspirin desensitization. Int J Cardiol 2010 [Epub ahead of print]. 6. Lee WL, Ho HH, Chan KW, Hai SH, Sin WC, Tam CC, Lam L, Chan HW. Successful use of endothelial progenitor cell capture stents in two cases of acute coronary syndrome complicated by major bleeding episodes. Int J Cardiol 2011;14:224 –226.
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7. Mauri L, Orav EJ, O’Malley AJ, Moses JW, Leon MB, Holmes DR, Teirstein PS, Schofer J, Breithardt G, Cutlip DE, Kereiakes DJ, Shi C, Firth BG, Donohoe DJ, Kuntz RE. Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents. Circulation 2005;111:321–327. 8. Aoki J, Serruys PW, van Beusekom H, Ong AT, McFadden EP, Sianos G, van der Giessen WJ, Regar E, de Feyter PJ, Davis HR, Rowland S, Kutryk MJ. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 2005;45:1574 –1579. 9. Duckers HJ, Soullié T, den Heijer P, Rensing B, de Winter RJ, Rau M, Mudra H, Silber S, Benit E, Verheye S, Wijns W, Serruys PW. Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent). Eurointervention 2007;3:350 –358. 10. Kaul U, Bhatia V, Ghose T, Gupta R, Kachru R, Singh G. Angiographic follow-up of Genous Bioengineered Stent in Acute Myocardial Infarction (GENAMI)—a pilot study. Indian Heart J 2008;60:532– 535. 11. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, Maccarthy PA, Van’t Veer M, Pijls NH. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55:2816 –2821. 12. Duckers HJ, Silber S, de Winter R, den Heijer P, Rensing B, Rau M, Mudra H, Benit E, Verheye S, Wijns W, Serruys PW. Circulating endothelial progenitor cells predict angiographic and intravascular ultrasound outcome following percutaneous coronary interventions in the HEALING-II trial: evaluation of an endothelial progenitor cell capturing stent. Eurointervention 2007;3:67–75. 13. Beijk MA, Klomp M, Verouden NJ, van Geloven N, Koch KT, Henriques JP, Baan J, Vis MM, Scheunhage E, Piek JJ, Tijssen JG, de Winter RJ. Genous endothelial progenitor cell capturing stent vs. the Taxus Liberte stent in patients with de novo coronary lesions with a high-risk of coronary restenosis: a randomized, single-centre, pilot study. Eur Heart J 2010;31:1055–1064. 14. Piscione F, Piccolo R, Cassese S, Galasso G, De Rosa R, D’Andrea C, Chiariello M. Effect of drug-eluting stents in patients with acute ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: a meta-analysis of randomised trials and an adjusted indirect comparison. Eurointervention 2010;5:853– 860. 15. Kaltoft A, Kelbaek H, Thuesen L, Lassen JF, Clemmensen P, Kløvgaard L, Engstrøm T, Bøtker HE, Saunamäki K, Krusell LR, Jørgensen E, Tilsted HH, Christiansen EH, Ravkilde J, Køber L, Kofoed KF, Terkelsen CJ, Helqvist S. Long-term outcome after drug-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: 3-year follow-up of the randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) Trial. J Am Coll Cardiol 2010;56:641– 645. 16. Brodie B, Pokharel Y, Fleishman N, Bensimhon A, Kissling G, Hansen C, Milks S, Cooper M, McAlhany C, Stuckey T. Very late stent thrombosis after primary percutaneous coronary intervention with bare-metal and drug-eluting stents for ST-segment elevation myocardial infarction: a 15-year single-center experience. JACC Cardiovasc Interv 2011;4:30 –38. 17. Rossi ML, Zavalloni D, Gasparini GL, Mango R, Belli G, Presbitero P. The first report of late stent thrombosis leading to acute myocardial infarction in patient receiving the new endothelial progenitor cell capture stent. Int J Cardiol 2010;141:e20 – e22.