Clinical and Angiographic Outcomes in Elderly ...

Original Contribution

Clinical and Angiographic Outcomes in Elderly Patients Treated with Endothelial Progenitor Cell Capture Coronary Stents: Results from a Prospective Single-Center Registry Salvatore Azzarelli, MDa, Alfredo R. Galassi, MDb, Giuseppe Grosso, MDc, Davide Tomasello, MDb, Barbara Campisano, MDb, Michele Giacoppo, MDa, Vincenzo Argentino, MDa, Francesco Amico, MDa, Antonio Fiscella, MDa ABSTRACT: Objective. To evaluate the outcomes in elderly patients treated with endothelial progenitor cell (EPC) capture stent, designed to promote rapid stent endothelialization, and dual-antiplatelet therapy for only 1 month. Background. Although some registries showed that drug-eluting stents have better clinical outcomes and can reduce reinterventions in comparison to bare-metal stents in elderly patients, the subsequent prolonged dual-antiplatelet therapy needed after drug-eluting stent implantation can likely be interrupted because of intolerance or comorbidities in this subset of patients, with high risk of stent thrombosis. Methods. One hundred consecutive patients ≥ 75 years with de novo lesions in native coronary arteries underwent EPC capture stent implantation. The study endpoints were major adverse cardiac events (MACE), binary restenosis and late lumen loss. Results. Mean age was 79 ± 3 years (78% male), 28% had diabetes, and 81% had non-ST-elevation acute coronary syndrome. A total of 134 lesions were treated, 69% were type B2/C, and 143 EPC capture stents were implanted (1.4 stents per patient). At 1-year follow up, clinical outcomes were: all-cause death, 8%; myocardial infarction, 2%; clinically-justified target lesion revascularization (TLR), 22%; MACE, 28%; and definite stent thrombosis, 2% (2 cases in the same patient). Angiographic 6-month follow up showed a binary restenosis rate of 35% and a late lumen loss of 0.94 ± 0.86 mm. Conclusion. This study suggests that EPC capture stent is safe and feasible in patients ≥ 75 years of age, but clinically justified TLR and binary restenosis were frequently observed. J INVASIVE CARDIOL 2010;22:594–598 Key words: endothelial progenitor cell, stent, elderly, percutaneous coronary intervention

Drug-eluting stents (DES) show better clinical outcomes1,2 and a reduction in repeat revascularization in comparison to bare-metal stents (BMS) in observational studies when used in the elderly.2,3 However, these data were not confirmed in randomized clinical trials because patients ≥ 75 years of age have been systematically underenrolled in these studies. Indeed, in the pivotal randomized From the aDivision of Cardiology, “Cannizzaro” Hospital, Catania; bClinical Division of Cardiology, “Ferrarotto” Hospital, University of Catania, Catania; and c“G.F. Ingrassia” Hygiene and Public Health Department, University of Catania, Catania, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted July 28, 2010, provisional acceptance given September 3, 2010, final version accepted September 27, 2010. Address for correspondence: Salvatore Azzarelli, MD, via Fò 24, 95037, San Giovanni La Punta, Catania, Italy. E-mail: [email protected]

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DES trials, the average patient age was 62 years, both with sirolimus- and paclitaxel-eluting stents.4 Moreover, in the elderly, the subsequent prolonged dual-antiplatelet therapy can likely be interrupted because of intolerance or comorbidities, with consequent high risk of stent thrombosis.5 The endothelial progenitor cell (EPC) capture stent is a bioengineered stent that rapidly forms an endothelial layer over the stent struts, which is intended to protect against thrombus and minimize restenosis, with only 1 month of clopidogrel treatment recommended.6 Therefore, the study hypothesis was to assess mid-term clinical and angiographic outcomes in patients ≥ 75 years who underwent a percutaneous coronary intervention (PCI) with EPC capture stents in a “real-world” scenario.

Methods Patient population. Consecutive patients aged ≥ 75 years with de novo lesions in native coronary arteries were prospectively enrolled in a single center. The exclusion criteria were ST-elevation myocardial infarction (STEMI), bypass conducts disease, left main coronary artery disease, use of more than 4 stents, in-stent restenosis, chronic total occlusion (thrombolysis in myocardial infarction [TIMI] flow 0, occlusion > 3 months), overlapping with another stent, contraindication to antiplatelet or statin therapy, reference vessel diameter < 2.5 mm, and severe concomitant diseases that strongly limit the life expectancy. Procedures and medications. All lesions were treated with Genous stents (OrbusNeich, Fort Lauderdale, Florida). A written informed consent to coronary intervention was obtained from all patients. The interventional strategy and the use of glycoprotein IIb/IIIa inhibitors were left entirely to the operator’s discretion. All patients received a pre-PCI intravenous bolus of heparin to maintain an activated clotting time of 250–300 seconds during the implantation. In addition, a loading dose of clopidogrel 600 mg and aspirin 300 mg was administered if the patient was not pretreated. Patients were thereafter maintained on clopidogrel 75 mg for 30 days and aspirin 100 mg indefinitely. Immediate statin therapy with atorvastatin 80 mg was initiated soon after the procedure and maintained for 30 days, and was then titrated according to the subsequent low-density lipoprotein cholesterol level. Coronary angiography. Lesions were classified by using the American College of Cardiology/American Heart Association The Journal of Invasive Cardiology

EPC Capture Stents in the Elderly Table 1. Baseline demographic and clinical characteristics of patients (n = 100).

Age (years) Male Diabetes mellitus Hypertension Hypercholesterolemia Current smoking Previous myocardial infarction Previous PCI/CABG Previous stroke/TIA Congestive heart failure Comorbidities Carotid or peripheral vascular disease Left ventricular ejection fraction (%) Clinical presentation Stable angina Unstable angina NSTEMI Acute myocardial infarction < 15 days

79 ± 3 78 28 67 42 20 26 11 11 7 18 13 48 ± 7 19 39 20 22

PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; TIA = transient ischemic attack; Comorbidities = chronic renal insufficiency (= creatinine ≥ 2 mg/dL), chronic obstructive pulmonary disease, liver disease, history of cancer; NSTEMI = non-ST-elevation myocardial infarction; AMI = acute myocardial infarction.

Table 2. Angiographic and procedural characteristics (visual estimation).

Number of diseased vessels (VD) (n = 164) Single-vessel disease Double-vessel disease Triple-vessel disease Treated coronary artery (n = 116) Left anterior descending artery Left circumflex artery Right coronary artery Lesion type (AHA/ACC) (n = 134) A B1 B2 C Lesion length (mm) Reference vessel diameter (mm) Stenosis (%) TIMI flow 0–1 pre-PCI Thrombus Lesions treated Lesions per patient Genous stents implanted Stents per patient Stent diameter (mm) Stent length (per lesion; mm) Overlapping stenting Predilatation Postdilatation Bifurcation GP IIb/IIIa inhibitors Genous stent failure Angiographic success Procedural success

49 (49%) 38 (38%) 13 (13%) 52 (45%) 30 (26%) 34 (29%) 11 (8%) 30 (23%) 49 (36%) 44 (33%) 16.6 ± 8.9 2.83 ± 0.32 85.2 ± 9.2 10 (7%) 12 (9%) 134 1.3 143 1.4 2.8 ± 0.3 19.8 ± 4.6 20 (15%) 109 (81%) 13 (10%) 10 (7%) 9 (9%) 4 (4%) 100 (100%) 96 (96%)

lesion morphology classification.7 Quantitative coronary angiography (QCA) was performed off-line by two operators not involved in the PCI using a validated edge-detection system (CMS, version 5.2; MEDIS, Leiden, The Netherlands). Reference vessel diameter (RVD), minimal lumen diameter (MLD) and percent diameter stenosis were measured preprocedure, postprocedure and at 6-month follow-up examination. Binary AHA/ACC = American Heart Association/American College of Cardiolrestenosis was defined as a reduction of ≥ 50% of the luminal diogy; TIMI = thrombolysis in myocardial infarction; PCI = percutaneous coronary intervention ameter within a previously stented segment, including 5 mm proximal or distal segments adjacent to the stent. Late lumen loss, defined as the difference Table 3. Quantitative coronary analysis. between post-procedural MLD and followup MLD were also computed. Angiographic Preprocedure Postprocedure Follow up Variable (n = 74) (n = 75) (n = 71) success was defined as the successful implantation of the Genous stent, with a stenosis < 20% 3.02 ± 0.70 3.02 ± 0.70 2.79 ± 0.73 Reference vessel diameter (mm) of the vessel diameter with TIMI flow grade 3. Minimal lumen diameter (mm) 0.91 ± 0.36 0.91 ± 0.36 1.85 ± 0.72 Procedural success was defined as angiographic Diameter stenosis (%) 69.05 ± 9.28 69.05 ± 9.28 34.41 ± 20.22 12.37 ± 7.98 12.37 ± 7.98 NA success in the absence of cardiac death, my- Lesion length (mm) NA NA NA ocardial infarction (MI) or target lesion revas- Acute gain (mm) NA NA 25 (35%) Binary restenosis cularization (TLR) during hospitalization. NA NA 0.94 ± 0.86 Late lumen loss (mm) Follow up. Discharged patients were scheduled for 1-, 6- and 12-month clinical fol- NA = not applicable low up and for 6-month angiographic follow up. We evaluated the occurrence of major adverse cardiac events at the hospital of admission according to standard criteria (in(MACE), target vessel revascularization (TVR) of the non-target creased levels of troponin or creatinine kinase-MB fraction in lesion, non-target vessel revascularization, non-cardiac death and association with chest pain and/or ischemic electrocardiographic definite stent thrombosis. MACE were defined as a composite of changes). Target lesion revascularization was defined as a recardiac death or non-fatal acute MI, or clinically justified TLR. peat intervention (percutaneous or surgical) to treat a luminal Acute MI during follow up was diagnosed by local cardiologists stenosis occurring within the stent or in the 5 mm proximal Vol. 22, No. 12, December 2010

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June 2007–November 2008 177 pts ≥ 75 years of age underwent PCI with stent implantation Patients Excluded (n = 77) 36 STEMI 11 bypass graft stenting 8 LM stenting 7 > 4 stents use 3 overlapping with other stent 3 CTO 3 ISR 2 contraindication to drug protocol 2 stent diameter < 2.5 mm 2 low life expectancy 100 patients were treated with EPC capture stents Figure 1. Flow diagram of study population. (STEMI = ST-segment elevation myocardial infarction; LM = left main coronary artery; CTO = chronic total occlusion; ISR = intrastent restenosis; EPC = endothelial progenitor cell).

30 Death or MI

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Clinically justified TLR n=22

MACE

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n=28

n=26

n=21

Definite ST

15 n=10

10 n=7

5

n=5 n=4 n=2 n=1

n=2

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Figure 2. Cumulative incidence of clinical outcomes at 1-month, 6month and 1-year follow up. MACE = major adverse cardiac events. 596

or distal segments adjacent to the stent. TLR was considered clinically justified when: 1) diameter stenosis was > 50% by visual estimation and either: a) a history of angina pectoris; or b) an abnormal result of any functional diagnostic test related to the target vessel; 2) TLR with diameter stenosis ≥ 70% by visual estimation also in the absence of the aforementioned ischemic signs or symptoms; and 3) TLR to treat a stent thrombosis. Target vessel revascularization of a non-target lesion was defined as a repeat intervention (percutaneous or surgical) to treat a luminal stenosis occurring in the same coronary vessel treated at the index procedure beyond the target lesion limits. Definite stent thrombosis (acute, subacute and late) includes angiographic or post-mortem evidence of stent thrombosis according to the Academic Research Consortium recommendations.8 All patients were followed up by telephone interview and information about clinical outcomes was confirmed by review of hospital records or by referring physicians. Data on all repeat interventions and repeat hospitalizations were prospectively collected. Study endpoints. Primary safety endpoints were MACE, while primary efficacy endpoints were clinically justified TLR. Secondary efficacy endpoints were binary restenosis and late lumen loss. Statistical analysis. Because of the observational nature of this nonrandomized registry, no formal power calculations were conducted to determine the safety and efficacy of the stent. The analysis was performed according to the intention-to-treat principle and included all patients initially enrolled in the study. Statistical analysis was performed using SPSS for Windows, Version 17.0 (SPSS, Inc., Chicago, Illinois). Categorical variables were presented as frequency of occurrence and percentages, and were analyzed with the chi-square test. Continuous data are presented as means and standard deviations, and were analyzed by Student’s t-test. All tests were two-tailed, with alpha levels of 0.05 considered significant. A logistic regression model was used to determine independent predictors of MACE and clinically justified TLR at 1-year clinical follow up, and binary restenosis at 6-month angiographic follow up by using all baseline and procedural characteristics listed in Tables 1 and 2. In all cases, p-values < 0.05 were considered significant.

Baseline characteristics and procedural data. Among 1,080 consecutive patients who underwent PCI with stent implantation between June 2007 and November 2008 in our tertiary referral hospital, 177 (16%) were ≥ 75 years of age. Overall, 100 patients were consecutively enrolled in the registry. Figure 1 presents the detailed selection algorithm. Clinical, angiographic and procedural characteristics are shown in Tables 1 and 2. Mean age was 79 ± 3 years, 78% of the patients were male, 28% had diabetes, 26% had a previous MI, 81% were admitted with an acute coronary syndrome and 69% of the lesions were type B2/C. We treated 134 lesions (1.3 lesions/patient) with 143 EPC capture stents (1.4 stents/patient). In 4 patients, the delivery system could not cross the target lesion; 6 conventional BMS (cobalt-chrome) were implanted The Journal of Invasive Cardiology

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in these patients. Angiographic success was achieved in all patients, while procedural success was achieved in 96 patients (3 patients died and 1 had TLR during the index hospitalization due to stent thrombosis). Clinical outcomes. Clinical follow up was 100% complete. Figure 2 provides an overview of the cumulative clinical outcomes at 1 month, 6 months and 1 year. A total of 8 deaths occurred, 5 of which were cardiac deaths. Three patients died during the index hospitalization; all of them were admitted with a non-ST-elevation MI (NSTEMI) and presented with poor left ventricular function (2 died the same day of the procedure and the other died on day 2 as a result of progressive hemodynamic deterioration). An 80-year-old male with diabetes, previous MI and poor left ventricular function suffered sudden cardiac death 6 days after hospital discharge. The last cardiac death occurred suddenly in another 80-year-old male with diabetes 11 months after his index hospitalization. A total of 2 non-fatal acute MIs occurred. One patient had an ST-elevation MI (STEMI) in a territory correlated to the target vessel, but at angiography the thrombotic occlusion was distal to the Genous stent, and the patient underwent a TVR of the non-TLR. The second non-fatal acute MI was an NSTEMI attributable to stent thrombosis of a complex bifurcated lesion (left anterior descending coronary artery/first diagonal) treated using 4 Genous stents with a T-stenting technique. The thrombosis occurred 45 days after hospital discharge, 14 days after clopidogrel discontinuation. The same patient had stent thrombosis 28 hours after stent implantation. In this 75-year-old female, whose results were affected by genetic thrombophilia, we initiated indefinite dual-antiplatelet therapy and she was asymptomatic at 1-year follow up. A total of 22 clinically justified TLRs were performed, the majority of them (19/22) during the 6-month angiographic follow-up period. In all cases, the reintervention was performed percutaneously with success; 19 patients (86%) were treated with balloon angioplasty alone and 3 patients (14%) were treated with in-stent implantation of a DES. TVR non-TLR and non-TVR were necessary in 3 and 9 patients, respectively. Six-month angiographic outcomes. Scheduled coronary angiography at 6 months was available for 70/96 living patients (73%). QCA data are presented in Table 3. Of note, binary restenosis occurred in 22/61 patients (36%) and 25/71 lesions (35%), and late lumen loss was 0.94 ± 0.86 mm. On the basis of the Mehran classification,9 there were 3 type IB (12%) restenoses, 15 were type IC (60%), 1 was type ID (4%) and 6 were type II (24%). In 19 cases (76%), the restenosis was between 50–69%, and was ≥ 70% in the remaining 6 (24%). Among the 26 patients pretreated with a statin for at least 2 weeks prior to the PCI and the 35 patients not pretreated, late lumen loss was 1.01 ± 0.83 mm and 0.88 ± 0.87 mm, respectively (p = 0.54). Additional analyses. The proportional hazard model demonstrated that only the number of stents implanted was a significant predictor of both MACE and clinically justified TLR at 1-year follow up (hazard ratio: 1.90; 95% CI: 1.03–3.49; Vol. 22, No. 12, December 2010

p = 0.03; and hazard ratio: 2.25; 95% confidence interval: 1.17–4.32; p = 0.015, respectively).

Discussion This study is the first “real-world” experience with EPC capture coronary stents in a population of patients ≥ 75 years of age. The main finding is that this stent can be safely used in elderly patients, as shown in the present study where there was a high prevalence of acute coronary syndromes, and only 1 month of dual-antiplatelet therapy was administered. However, although clopidogrel was safely withdrawn after EPC capture stent implantation, the restenosis rate was not inferior to that of a BMS. Among the population ≥ 75 years of age, the fastest-growing segment in the Western industrial countries is the high prevalence of coronary artery disease treated with PCI. There are few data for this patient population from randomized trials regarding stent choice (bare-metal or drug-eluting), because elderly patients have been systematically underenrolled in randomized trials.4 Some registries2,3 showed that in elderly patients, DES can reduce the need for repeated interventions compared with BMS. Since the procedural risk for elderly patients undergoing PCI is higher than for younger patients, a reduction in repeat revascularizations should reduce the risk in these patients.10 Indeed, in contrast to clinical trial results, DES were associated with better clinical outcomes such as lower acute MI and improved survival rates.1,2 However, prolonged dual-antiplatelet therapy is needed to reduce adverse cardiac events after placement of a DES.11 This presents two problems in elderly patients: 1) vast registry data show that advanced age is strongly associated with excessive bleeding12,13 and need for blood transfusion;14 and 2) a concomitant disease or the need for non-cardiac surgery can likely result in the premature discontinuation of the antiplatelet drugs, with the consequent risk of stent thrombosis.5 In this setting, it is interesting to note that the stent is coated with murine monoclonal antihuman CD34+ antibodies, which can capture circulating EPCs to the stent surface, thus inducing the rapid establishment of a functional endothelial layer. Indeed, we prescribed a high dose of atorvastatin immediately after the procedure, since statins are among drugs that have been shown to promote survival, migration, and differentiation of adult bone marrow-derived EPCs, thus enhancing EPC recruitment to sites of neovascularization.15 However, although Duckers et al16 showed a correlation between lower late lumen loss and pretreatment with statins at least 2 weeks prior to the PCI in the HEALING-II trial, we did not find any difference between the patients pretreated versus those who were not in terms of late lumen loss (1.01 ± 0.83 mm versus 0.88 ± 0.87 mm, respectively; p = 0.54). The HEALING-FIM study6 showed the safety and feasibility of this stent for the treatment of de novo coronary artery disease in 16 patients with stable angina and simple lesions, with a late lumen loss of 0.63 ± 0.52 mm. The HEALING-II study showed similar results in 63 patients, with a late lumen loss of 0.78 ± 0.39 mm and percent in-stent volume obstruction of 22.9 ± 13.7%.16 In the 597

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“real world” with more complex lesions and patients, Miglionico et al17 showed satisfactory clinical outcomes in 80 highrisk patients, although in the angiographic cohort of 31 patients there was a late loss of 0.88 ± 0.62 mm. In addition, Co et al18 studied 120 STEMI patients and confirmed that the stent is also feasible and safe during primary PCI, but this study lacks angiographic information to evaluate the late lumen loss. However, Kaul et al19 studied 10 STEMI patients and showed a late lumen loss of 0.97 ± 0.94 mm at angiographic follow up. In accordance with the literature, our study confirms the safety of the EPC capture stent, but underlines that the efficacy is similar to a BMS. Indeed, a hard event rate (death/non-fatal MI) of 10% at 1 year is similar to that shown in the registries,14 and a clinically justified TLR rate of 22% at 1 year, a binary restenosis rate of 35%, and a late lumen loss of 0.94 ± 0.86 mm observed at 6-month angiographic follow up were similar to that of a BMS.4 Interestingly, Piscione et al20 studied 30 patients who underwent EPC coronary stent implantation 17.2 ± 3.9 days before upcoming undeferable non-cardiac surgery; in these patients, dual-antiplatelet therapy was interrupted after 12.2 ± 3.9 days, without cardiac events at 30-day follow up. Also, our data suggest a role for the EPC capture stent in acute patients requiring percutaneous coronary revascularization who may have problems with prolonged dual-antiplatelet therapy, such as those scheduled for surgery or suffering from hemorrhagic diseases. Further research should focus on the use of EPC capture coronary stents in association with early interruption of dual-antiplatelet therapy. Of note, although our registry showed a stent thrombosis rate of 2% at 1 year, the 2 episodes of stent thrombosis in the same patient seemed to be related to the complex coronary lesion and genetic thrombophilia, rather than the EPC capture stent. Study limitations. The major limitation is that this is a singlecenter, observational registry. However, it is the first “real-world” experience with the EPC capture coronary stent in a population of patients ≥ 75 years of age. Moreover, the high prevalence of men included in the study (78%) may limit assessment of the efficacy of the stent in female patients. However, the higher percentage of male patients is generally consistent in other studies as well.

Conclusion This study suggests that the EPC capture stent is safe and feasible for the treatment of coronary artery disease in patients ≥ 75 years of age, despite only 1 month of dual-antiplatelet therapy, although clinically justified TLR and binary restenosis were

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frequently observed. Large randomized studies with long-term follow up are needed to evaluate the clinical role of the EPC capture stent in percutaneous coronary interventions.

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