来自中国的最新临床试验公布 作者:黄榕翀 周旭晨
  3月19日下午4:30至6:00,CIT 2009最吸引众多专家厂商眼球的一场便是CIT最有特色的最新临床试验报告。近年来,随着中国国产介入器械的迅速发展和中国介入心脏病学专家介入水平的提高,中国开始积极参与大型国际临床研究。今年CIT期间,来自中国的5位专家报告了其所在中心领导的5项临床研究结果。
首先高润霖院士报告了I-LOVE-IT(TIVOLI生物降解涂层西罗莫斯洗脱支架比较ENDEAVOR左他莫斯洗脱支架的前瞻性多中心临床试验:8个月造影和1年临床随访结果)。 TIVOLI生物降解涂层西罗莫斯洗脱支架使用钴铬合金骨架,PLGA生物可降解涂层,前期动物研究结果显示1个月内皮可以覆盖支架表面,且没有明显狭窄。为了进一步  研究TIVOLI支架在“真实世界”中是否安全有效,包括阜外心血管病医院在内的12家医疗中心共入选了324例冠心病患者,分为TIVOLI支架治疗组(n=168)和ENDEAVOR支架治疗组(n=156),给予氯吡格雷口服至少6个月、阿司匹林长期口服抗血小板药物治疗。
  入选患者均为靶病变至多2处, DS%不低于70%, 除外1周内心肌梗死、 心功能下降、严重出血性疾病等情况。主要研究终点是240天支架内晚期丢失(In-stent Late Loss),次要终点包括节段内晚期丢失、支架及节段内界限性狭窄、1年MACE发生率以及器械操作失败等。该研究共有83.2%的患者完成8个月造影,99.7%患者完成1年临床随访,计划随访5年。分析入选患者基本资料发现,与ENDEAVOR支架治疗组相比,TIVOLI支架治疗组糖尿病、高血压、不稳定心绞痛患者以及既往PCI治疗患者比例更高,病变数也多于ENDEAVOR支架治疗组(1.43 比 1.27, P=0.0018),病变长度以及置入支架长度更长(P<0.05),说明病变更为复杂。8个月QCA结果显示主要终点In-stent Late Loss TIVOLI治疗组和ENDEAVOR支架治疗组分别是0.25±0.33mm和0.57±0.55mm,TIVOLI治疗组下降了56%。TIVOLI治疗组节段内晚期丢失(2.9% 比8.6%)、支架内及节段内界限性狭窄均明显低于ENDEAVOR支架治疗组。1年临床随访结果显示,两组间MACE发生率、生存率未见明显差别(P=0,14),但是TLR和再次MI发生率TIVOLI治疗组明显低于对照组(P=0.0495)。
  两组患者应用双联抗血小板药物治疗率6个月时未见差别,但12个月时ENDEAVOR支架治疗组应用比例高于TIVOLI支架治疗组。TIVOLI支架组患者有1例患者发生支架内血栓形成(24h-30d),但与对照组相比,没有统计学意义。因此,研究者认为,与ENDEAVOR支架相比,TIVOLI支架在8个月时支架内晚期丢失更少,1年临床结果证实安全有效。当然,该研究未进行随机分组,可能会存在一定偏差,这还需要进一步研究证实。
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来自Chinese Medical Journal 2011;124(6):811-816
Original article
A prospective multicenter parallel-controlled trial of TIVOLI biodegradable-polymer-based sirolimus-eluting stent compared to ENDEAVOR zotarolimus-eluting stent for the treatment of coronary artery disease: 8-month angiographic and 2-year clinical follow-up results
XU Bo, DOU Ke-fei, HAN Ya-ling, Lü Shu-zheng, YANG Yue-jin, HUO Yong, WANG Le-feng, CHEN Yun-dai, WANG Hai-chang, LI Wei-min, CHEN Ji-yan, WANG Lei, WANG Yong, GE Jun-bo, LI Wei and GAO Run-lin
Keywords: TIVOLI stent; biodegradable polymer; sirolimus-eluting stent; clinical outcome

Background Available drug-eluting stents (DES) have achieved great success in reducing restenosis rates. Recently, investigators have demonstrated that the durable polymer carrier plays a significant role in DES-related hypersensitive reaction and delays vessel healing. TIVOLI stent is a novel sirolimus-eluting coronary stent with biodegradable coating containing sirolimus and polylactic-co-glycolic acid (PLGA) polymer. The present study sought to evaluate the effectiveness and safety of the TIVOLI biodegradable-polymer-based sirolimus-eluting stent in treating patients with coronary artery disease.

Methods A prospective, multicenter clinical trial comparing TIVOLI biodegradable coated sirolimus-eluting stent with ENDEAVOR zotarolimus-eluting stent was conducted in 324 patients (TIVOLI group: 168 patients; ENDEAVOR group: 156 patients) at 12 centers in China to demonstrate the non-inferiority of in-stent late loss with TIVOLI stent compared to ENDEAVOR stent in subjects with a maximum of two de novo native coronary artery lesions (lesion length ≤40 mm, reference vessel diameter 2.25–4.00 mm). The primary end point was angiographic in-stent late loss at 8-month. The secondary end points were clinical outcomes at 2 years, including major adverse cardiac events (cardiac death, myocardial infarction, or target-lesion revascularization) and stent thrombosis.

Results Angiographic late lumen loss at 8 months in the TIVOLI group was superior to the ENDEAVOR group (in-stent (0.25±0.33) mm vs. (0.57±0.55) mm, diff (95% CI) –0.23 (–0.32, –0.14), P <0.0001; in-segment (0.25±0.33) mm vs. (0.42±0.55) mm, diff (95% CI) –0.13 (–0.23, –0.02), P=0.0083). The rate of in-stent binary restenosis at 8 months was reduced from 8.6% in the ENDEAVOR group to 2.9% in the TIVOLI group (P=0.0229). Compared to ENDEAVOR stent, TIVOLI stent resulted in a significant reduction in target-lesion revascularization (4.2% vs. 9.6%, P=0.0495) at 2 years. The two-year major adverse cardiac events (MACE) rate was lower for the TIVOLI group, but not significantly different (6.6% vs. 10.9%, P=0.1630).

Conclusions TIVOLI was superior to ENDEAVOR stent with respect to late lumen loss at 8 months, and it yielded both lower rates of angiographic binary restenosis at 8 months and target lesion revascularization (TLR) at 2 years. The MACE rate at 2 years was comparable in both groups.Chin Med J 2011;124(6):811-816

Use of drug-eluting stents (DES), especially sirolimuseluting stent, is associated with more than slightly better efficacy outcomes as compared to that of bare metal stent (BMS).1-4 However, thrombosis remains the most critical issue concerning modern DES utilization.5,6 Recently, investigators have demonstrated that durable polymer carrier plays a significant role in DES-related hypersensitivity reaction and delayed vessel healing, which may contribute to stent thrombosis.7-9 To address this issue, a new generation DESs using biodegradable polymer carrier, which leave


DOI: 10.3760/cma.j.issn.0366-6999.2011.06.003 Cardiac Catheterization Laboratory (Xu B), Department of Cardiology (Dou KF, Yang YJ and Gao RL), Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, China Department of Cardiology, Shenyang Northern Hospital, Shenyang, Liaoning 110015, China (Han YL) Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China (Lü SZ) Department of Cardiology, Peking University First Hospital, Beijing 100044, China (Huo Y) Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China (Wang LF) Department of Cardiology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China (Chen YD) Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China (Wang HC) Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China (Li WM) Department of Cardiology, Guangdong Provincial Cardiovascular Institute, Guangzhou, Guangdong 510080, China (Chen JY) Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China (Wang L) Department of Cardiology, China-Japan Friendship Hospital, Beijing 100029, China (Wang Y) Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China (Ge JB) National Center for Cardiovascular Diseases of China, Beijing 100037, China (Li W) Correspondence to: Prof. GAO Run-lin, Department of Cardiology, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100037, China (Tel: 86-10-88398666. Fax: 86-10-68333879. Email: gaorunlin@263.net) XU Bo and DOU Ke-fei contributed equally to this study.

a residual BMS after full degradation of these polymers into carbon dioxide and water ensuring complete drug release, has emerged as a new strategy.10,11 The present study sought to evaluate effectiveness and safety of TIVOLI biodegradable-polymer-based, sirolimus-eluting stents (Essen Technology Beijing Co. Ltd., China) in treating patients with coronary artery disease.

METHODS Study design and patient population This was a prospective, parallel controlled, multicenter clinical trial (at 12 centers in China), which was performed from June 2007 to June 2008. The study protocol was approved by the hospital ethic committees and monitored by Division of Biometrics, Center for Cardiovascular Disease Control and Prevention, Ministry of Health, China. Written informed consent was obtained from all patients.

To demonstrate the non-inferiority of TIVOLI biodegradable-polymer-based, sirolimus-eluting stent to the ENDEAVOR zotarolimus-eluting stent concerning safety and efficacy, 324 patients were prospectively enrolled in the study. One hundred and sixty-eight patients (with 216 lesions) received TIVOLI stents and 156 patients (186 lesions) with ENDEAVOR stents served as parallel control.

The inclusion criteria were as follows: maximum of two de novo native coronary artery lesions; reference vessel diameter 2.25–4.00 mm, lesion length ≤40 mm at target lesion; and patient willing to sign informed consent and receive clinical and angiographic follow-up. The exclusion criteria were: acute myocardial infarction within 1 week; left main coronary artery disease; total occlusion lesion (TIMI 0 grade); angiographic thrombus containing lesion; lesion unable to be pre-dilated due to severe calcification or tortuosity; true bifurcation with side branch diameter >2.5 mm; NYHA classification >grade 3 or left ventricular ejection fraction (LVEF) <40%; restenotic lesion; patient underwent percutaneous coronary intervention (PCI) in 6 months or PCI on target lesion; and life expectancy <12 months.

Study device TIVOLI stent (Essen Technology Beijing Co. Ltd.) (Figure 1) is a new sirolimus-eluting coronary stent with a unique open-cell design and thin wall (80 microns) cobalt-chromium platform, combined with bioabsorbable coating containing sirolimus and polylactic-co-glycolic acid (PLGA) polymer. Kinetic release data indicate that about eighty percent of the drug in the coating releases in one month and full absorption of the coating takes place in six months. Histology data from animal study showed that the polymer carrier was associated with very low inflammation in porcine coronary vessels.

The stent lengths used were 10, 15, 18, 20, 21, 25, 30, 35, 40 mm with diameters of 2.25, 2.50, 2.75, 3.00, 3.50, 4.00 mm.

Procedural and post-interventional practices Interventional strategy was decided by the interventional cardiologists. Administration of loading doses of 300 mg clopidogrel and 300 mg aspirin 24 hours before the procedure was mandatory. At least 6 months of clopidogrel (75 mg/d) and aspirin (100 mg/d) indefinitely were prescribed to all patients.

Follow-up and study endpoints Clinical follow-up was scheduled at 30, 90, 180, 270, 360, 720 days after the initial procedure. Angiographic follow-up was obtained at baseline and 240 days. The primary end point was 240-day late lumen loss (LLL). Secondary endpoint included in-stent and in-segment restenosis at 240-day angiographic follow-up, major adverse cardiac events (MACE) (the composite of death, myocardial infarction (MI), target lesion revascularisation (TLR)) and stent thrombosis rate during the clinical follow-up.

MI was defined as elevation of creatine kinase (CK)-MB level >3 times the normal range with or without new pathological Q-wave in electrocardiogram. Procedural success was defined as achieving <20% residual stenosis and TIMI3 flow for all lesions attempted without major clinical complication. Stent thrombosis was defined as either

definite or probable stent thrombosis according to Academic Research Consortium (ARC) definition.12

Coronary angiograms were obtained in multiple views after an intracoronary injection of nitroglycerin preprocedure, post-procedure and at 240-day angiographic follow-up. Quantitative coronary angiography (QCA) was performed by an independent core laboratory. Late lumen loss was defined as the difference between the minimal lumen diameter (MLD) after procedure and at 240-day angiographic follow-up. Restenosis was defined as ≥50% diameter stenosis at follow-up, and was classified as in-stent if inside of the stent or in-segment if located at the stent segment or up to 5 mm proximal or distal to the stents.

Statistical analysis The primary objective was to demonstrate the non-inferiority of TIVOLI stent compared to ENDEAVOR. The in-stent LLL of (0.61±0.46) mm was reported in the ENDEAVOR II study,13 and we assumed that the ENDEAVOR group in this study group would have the same LLL level. The non-inferiority margin was set at 0.2 mm. Using a 2-sided test with an alpha level of 0.05 and assuming a 20% loss to angiographic follow-up, we calculated that 320 patients would yield more than 90% power to detect non-inferiority. On the other hand, if the mean difference in in-stent late loss at 8 months was greater than 0.2 mm (TIVOLI superior to ENDEAVOR), a superiority conclusion would be obtained.

Continuous variables were expressed as mean ± standard deviation (SD) and compared through the use of the Student’s unpaired t test. Categorical variables were expressed as percentages and the chi-square test was used for comparison. The analysis of covariance (ANCOVA) was used as the primary analysis for LLL. The pre-specified covariates were the post procedure MLD and the investigation site. Cumulative incidence of MACE at 2 years was estimated by the Kaplan-Meier method and compared by use of the log-rank test. All statistical tests were 2 sided, and a value of P <0.05 was considered significant. All analyses were performed with SAS (9.13 System, SAS Institute, Cary, NC, USA.).

RESULTS Baseline and procedure characteristics Baseline patient characteristics were comparable in the two groups, except for older and fewer patients with prior MI and unstable angina pectoris and lower average lesion number per patient in the ENDEAVOR group (Table 1). Analyses of lesion characteristics and QCA revealed that patients in the TIVOLI group had smaller vessel size, longer lesion, longer stent length, and lower in-stent acute gain (Table 2). Device success rate was 100% in both groups.

Angiographic follow-up A total of 70.8% patients (119/168, with 175 lesions) in the TIVOLI group and 67.3% patients (105/156, with 128 lesions) in the ENDEAVOR group underwent angiographic follow-up at 240 days after initial procedure (Table 3). LLL was significantly lower in

the TIVOLI group (in-stent (0.25±0.33) mm vs. (0.57±0.55) mm, diff (95% CI) –0.23 (–0.32, –0.14), P <0.0001; in-segment (0.25±0.33) mm vs. (0.42±0.55) mm, diff (95% CI) –0.13 (–0.23, –0.02), P=0.0083). In the TIVOLI group, in-stent restenosis rate was significantly lower to that in the ENDEAVOR group (2.9% vs. 8.6%, P=0.0229).

Clinical outcome All patients in both groups completed clinical follow-up (Table 4). Cumulative incidence of MACE at 2-year was similar in the two groups (6.6% vs. 10.9%, P=0.1630), but MACE rate in the TIVOLI group tended to be lower. The same result was obtained using the Kaplan-Meier method to compare the incidence of MACE between the two groups (Figure 2). However, we found significantly lower TLR arte in the TIVOLI group (4.2% vs. 9.6%, P=0.0495) which might account for the trend toward lower MACE rate in the TIVOLI group.

Although the incidence of stent thrombosis was comparable in the two groups, one definite stent thrombosis was reported in the TIVOLI group at 30 days follow-up. Other endpoints were comparable between groups.

DISCUSSION Because permanent polymer coatings may have proinflammatory and thrombogenic potential, present DES research has been focusing on utilization of biodegradable polymer coating or on a completely polymer-free DES platform. The present study is the first clinical trial concerning the use of biodegradablepolymer- based, sirolimus-eluting stents in treating patients with coronary artery disease in China. The results showed that TIVOLI biodegradable-polymer-based, sirolimus-eluting stent was associated with better efficacy and similar safety as compared to ENDEAVOR zotarolimus-eluting stent.

The primary endpoint of the study, LLL, was markedly lower in the group that received TIVOLI biodegradable-polymer-based, sirolimus-eluting stents compared with ENDEAVOR zotarolimus-eluting stents (in-stent: (0.25±0.33) mm vs. (0.57±0.55) mm, P <0.0001; in-segment: (0.25±0.33) mm vs. (0.42±0.55) mm, P=0.0083). A previous study also had shown similar LLL at 8 months angiographic follow-up after ENDEAVOR zotarolimus-eluting stents implantation (in-stent: (0.61±0.46) mm; in-segment: (0.36±0.46) mm).13 The secondary endpoints, angiographic restenosis and TLR, were significantly lower for TIVOLI stent. On the other hand, cumulative incidence of MACE at 2 years was similar in the two groups (6.6% vs. 10.9%, P=0.1630), but MACE in the TIVOLI group tended to be lower. The significantly lower LLL secondary to different drug release kinetics may probably underlie the lower risk of reintervention and restenosis associated with use of TIVOLI biodegradable-polymer-based, sirolimus-eluting stents.

In terms of safety, incidence of death, MI, and stent thrombosis was comparable between the two groups in the present study. There was one patient in the TIVOLI group who suffered a definite stent thrombosis with Q-wave MI after 2-week discontinuation of aspirin because of stomach discomfort. One case of cardiac death in TIVOLI group was not related to stent implantation. Because of the limited study population and non-randomized design, to evaluate safety after TIVOLI stent implantation, much larger patient groups, a randomized design, and longer clinical follow-up are warranted.

To diminish the pro-inflammatory and thrombogenic potential of the permanent polymer coating of existing DES, a completely polymer-free DES platform has been envisioned as an alternative. However, in a recently published trial, a DES platform without a polymer coating, designed to elute paclitaxel or sirolimus, failed to show non-inferiority compared to first-generation DES with durable polymer coating.14,15 Mehilli et al15 also demonstrated that a polymer-free stent eluting sirolimus provided an inferior efficacy, while a biodegradablepolymer stent eluting sirolimus was at least as effective as the permanent polymer sirolimus-eluting stent in terms of

anti-restenotic efficacy. Hence, current polymer-free stent platforms for drug release may have a less bright future but biodegradable polymer stents may provide both effective anti-proliferation and minimization of inflammation caused by polymer.

TIVOLI stent is a domestic new sirolimus-eluting coronary stent with cobalt-chromium platform, combined with bioabsorbable coating containing sirolimus and PLGA polymer. Full absorption of the coating takes place in six months. Histology data from animal study showed that the polymer carrier was associated with very low inflammation in porcine coronary vessels.16 Although only 66.5% patients completed 1-year dual anti-platelet treatment, the TIVOLI group showed better efficacy and similar safety as compared to the ENDEAVOR group. The potentially shorter duration of dual antiplatelet therapy would be welcome, especially in developing countries where the cost of such therapy is one important limiting factor for DES usage.

The limitations of the study are as follows: (1) the control group was selected from patients who underwent ENDEAVOR implantation at the same period as TIVOLI group enrollment. (2) Patients included in the study were strictly selected by angiographic and clinical characteristics. (3) It is a small-scale trial. In the future, a large-scale randomized trial in real-world practice is needed to determine the long-term efficacy and safety of this novel sirolimus-eluting coronary stent with bioabsorbable coating.

In conclusion, based on the present study, TIVOLI biodegradable polymer based sirolimus eluting stent appears to be a safe, effective and feasible treatment option for patients with coronary artery disease.


Appendix: Clinical trial organization: Principal investigator: GAO Run-lin, Cardiovascular Institute and Fuwai Hospital. Independent data safety and monitoring: LI Wei, Division of Biometrics, Center for Cardiovascular Disease Control and Prevention, Ministry of Health, China. Core angiographic and IVUS laboratory: Cardiac Catheterization Laboratory, Cardiovascular Institute and Fuwai Hospital (XU Bo). Clinical sites: Cardiovascular Institute and Fuwai Hospital (GAO Run-lin, CHEN Ji-lin, YANG Yue-jin, QIAO Shu-bin, QIN Xue-wen, LIU Hai-bo, WU Yong-jian, LI Jian-jun, CHEN Jue, YOU Shi-jie and DAI Jun); Beijing Anzhen Hospital, Capital Medical University (YAN Hong-bing, ZHOU Yu-jie, CHEN Fang and LI Zhi-zhong); Peking University First Hospital (HUO Yong, LI Jian-ping and CHEN Ming); Beijing Chao-Yang Hospital, Capital Medical University (WANG Le-feng, WANG Hong-shi and GE Yong-gui); Beijing Friendship Hospital, Capital Medical University (WANG Lei); Chinese People’s Liberation Army General Hospital (YANG Ting-shu); China-Japan Friendship Hospital (WANG Yong and LI Xian-lun); First Clinical College of Harbin Medical University (LI Wei-min, ZHOU Li-jun, YANG Shu-sen and LI Yue); Shenyang Northern Hospital (HAN Ya-ling, JING Quan-min and WANG Shou-li); Xijing Hospital, Fourth Military Medical University (WANG Hai-chang and Lü An-lin); Zhongshan Hospital, Fudan University (GE Jun-bo, WANG Qi-bing and QIAN Ju-ying); Guangdong Cardiovascular Institute, Guangdong General Hospital (CHEN Ji-yan, TAN Ning, LI Guang, ZHOU Ying-ling, HUANG Wen-hui, NI Zhong-han and CHEN Zhu-jin).

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(Received December 7, 2010) Edited by WANG Mou-yue and LIU Huan

 

 
 
 


 
 

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