Yan, LI; Cheng-xiang, LI; Hai-chang, WANG; Bo, XU; Wei-yi, FANG; Jun-bo, GE; Wei-min, WANG; Shu-bin, QIAO; Jack-P, CHEN; Wen-kuang, SHEN; Hong, JIANG; Hong-liang, CONG; Xiao-qun, PU; Yong-wen, QIN; Hui-gen, JIN; Yu, CAO; He, HUANG; Investigators, FIREMAN

Section Editor(s): WANG, Mou-yue; LIU, Huan

The efficacy of drug-eluting stents (DES) in reducing target lesion revascularization (TLR) and subsequent major adverse cardiac events (MACE) has been proved in previous studies.^1-4 Off-label application of DES in daily practice was demonstrated with higher adverse events comparing to on-label usage of DES in treating patients with coronary artery disease.^5,6 Increased risk of stent thrombosis (ST) was reported in previous studies in the setting of off-label usage of DES. The efficacy and safety of Firebird sirolimus-eluting stent (SES) (Microport Medical, Shanghai, China) was previously confirmed in the “Firebird in China (FIC)” registry.⁷ However, most of the lesion subsets included the FIC registry were simple and remained with on-label indication.

The FIREMAN prospective, national-wide multicenter registry was designed to evaluate the efficacy and safety of Firebird SES in treating patients with complex coronary lesions in Chinese patients in current era. Here we reported the one-year clinical outcomes and eight-month non-mandatory angiographic results in more than half of the patients.

METHODS

Firebird SES

The Firebird SES (MicroPort Medical) consists of a balloon-expandable stainless steel stent with a polymeric EVAC matrix coating. The concentration of sirolimus coated on the stent was 160 μg/mm² (loaded drugs/stent surface area). Stents were available from 13, 18, 23, 29 and 33 mm in length and 2.5, 3.0, 3.5, 4.0 mm in diameters, respectively.

Patient selection

A total of 1078 consecutive patients with stable or unstable angina, as well as documented silent ischemia, underwent Firebird SES implantation between September 2006 to July 2007 at 45 hospitals throughout China were screened. Forty-nine patients were excluded according to the exclusion criteria. All of these 45 hospitals hade moderate- to high-volume percutaneous coronary intervention (PCI) per year (over 500/year). Patients were included if the coronary angiography found at least 1 of 9 following complex characteristics: (1) multivessel diseases, (2) long lesions with length ≥30 mm, (3) small vessel diseases with reference vessel diameter ≤2.5 mm by visual estimation, (4) bifurcation lesions, (5) chronic totally occluded lesions (≥3 months), (6) aortic ostial lesions, (7) severe calcification or severe angulation (location of target lesion >45°), (8) unprotected left main lesions, (9) in-stent restenosis after bare metal stent. The exclusion criteria included recent myocardial infarction (MI) (≤1 month), left ventricular ejection fraction ≤30%, renal insufficiency (serum creatinine ≥20 mg/L), bypass graft lesions, and those were treated with other types of stent. All patients signed written informed consent, and the study was conducted under institutional ethics committee approval.

Procedure and adjunctive medical therapy

PCI was performed using standard technique via the radial or femoral approach in all the cases. Prior to PCI, all patients were administered 300 mg of aspirin and 300-600 mg of clopidogrel, if not already on a maintenance dose. Dual antiplatelet therapy was recommended for a minimum of 12 months. During the procedure, patients were anticoagulated with a bolus dose of unfractionated heparin (100 U/kg), as well as subsequent additional heparin to achieve an activated clotting time of 250 to 300 seconds. Adjunctive devices and platelet glycoprotein IIb/IIIa inhibitors were utilized at operator's discretion.

Definitions and study endpoints

The primary end points were composite MACE at one year, including cardiac death, non-fatal MI, and TLR. Cardiac death was defined as all deaths for which a noncardiac cause could not be demonstrated. Non-fatal MI was defined as ischemic symptoms and an elevation of creatinine kinase-MB ≥2 times the upper normal value (25 IU) with or without ST-segment elevation or development of Q-waves. Furthermore, TLR was defined as any symptom-driven revascularization, either coronary artery bypass graft (CABG) or repeated PCI for a stenosis or occlusion within the stent or within the 5-mm segments proximal or distal to the stent. Revascularization of ≥70% stenosis in the absence of ischemic signs or symptoms also was considered clinically driven.

Secondary end points included target vessel revascularization (TVR), ST, or stroke at 1, 6, 12, 24, and 36 months. Angiographic end points included binary restenosis and late lumen loss at 8 months. TVR was defined as revascularization (either CABG or repeat PCI) of the stented vessel, including repeat TLR. Angiographic success was defined as a residual stenosis <30% with a thrombolysis in MI (TIMI) grade 3 flow. ST was defined according to the recommendations of the Academic Research Consortium (ARC) for definite and probable ST, as well as early (0-30 days), late (31 to 360 days), or very late (>360 days). Definite ST was defined as acute coronary syndrome with angiographic or autopsy evidence of partial or total thrombotic occlusion within the peri-stent region. Probable ST included any unexplained death within 30 days of stent implantation or MI in the treated vascular territory, in the absence of other obvious causes.⁸

Follow-up

All enrolled patients were evaluated at 1, 6, and 12 months post-implantation by outpatient personal or telephone interview. Continuing clinical follow-up at 18, 24, 30, and 36 months was planned. Angiographic follow-up at eight-month after index procedure was non-mandatory in the study design, but was encouraged in all patients regardless of the clinical symptoms.

Data management

Site monitoring was undertaken by an independent organization (CCRF (Beijing) Co. Ltd., China), and data management and statistical analysis were performed by an independent organization (Department of Statistics of the Fourth Military Medical University, Xi'an, China). An independent angiographic core laboratory (angiographic core laboratory of Fuwai Cardiovascular Hospital, Beijing, China) performed blinded angiographic analysis. All MACE were reviewed and adjudicated by an independent clinical events committee.

Statistical analysis

All analyses were based on the intention-to-treat principle. A “per-lesion” analysis was performed for all angiographic parameters in this report. Continuous variables are expressed as mean ± standard deviation (SD). Categorical data are expressed as percentages. Cox proportional hazards regression was used to identify independent predictors of 12-month secondary end point of ST. Kaplan-Meier survival curve analyses were used to demonstrate cumulative incidences of 12-month composite end points of cardiac death, MI, TLR, or ST. Variables of baseline characteristics including age, sex, weight, diabetes, hypertension, hyperlipidemia, and prior MI; as well as all nine complex anatomic subtypes were considered enter the multivariable analyses model as potential predictors. All statistical analyses were performed by use of SPSS (version 10.0, Chicago, USA). A P value <0.05 was considered to indicate statistical significance.

RESULTS

Baseline clinical and procedural characteristics

Baseline clinical, angiographic, and procedural features are shown in Tables 1 and 2. A total of 1029 eligible patients have mean age of (64.2±10.2) years. The ratio between male and female was 2.8:1. Hypertension and diabetes were reported in 669 (65.0%) and 235 (22.8 %), respectively. The mean lesion length and diameter stenosis were (23.7±14.4) mm and (76.2±13.9)%, respectively. Acute gain was (1.95±0.45) mm in-stent and (1.69±0.48) mm in-segment. A mean of 2.2 stents were implanted per patients, while 31.4% of patients received ≥three stents.

Table 1

Table 2

Complexity of lesions

The frequencies of specific complex coronary features are shown in Table 3. Long lesions, multi-vessel lesions, and small vessel lesions accounted for 59.2 %, 50.4 %, and 31.6 %, respectively (Table 3).

Table 3

One-year clinical outcomes

Clinical follow-up at 30 days, 6 months, and 12 months were completed for 100% (1029/1029), 99.5% (1024/1029), and 99.2% (1021/1029) of subjects, respectively. Cumulative event rates for the primary end point of MACE (cardiac death, non-fatal MI, and TLR) from 30 days to 12 months are shown in Table 4. At 6-month follow-up, cardiac mortality was 0.5% (5/1024); and incidence of non-fatal MI was 1.0% (10/1024). TLR was 0.3% (3/1024), with 100% repeat PCI and no CABG. Cumulative MACE rate was 1.6% (16/1024), and all-cause mortality was 0.8% (8/1024).

Table 4

By 12 months, the cumulative MACE remained relatively low at 5.1% (51/1021). There was slight increase in cardiac death and non-fatal MI to 0.6% (6/1021) and 1.1% (11/1021), respectively; while TLR increased from 0.3% to 3.4% during the second 6-month period. All-cause mortality was 2.0% (20/1021) (Table 4). MACE, cardiac death, non-fatal MI, and TLR-free survival curves are depicted in Figure 1. Cumulative MACE-free survival rate at one-year follow-up was 94.2 %, with specific cardiac death-free, non-fatal MI-free and TLR-free survival rates of 99.4%, 97.9%, and 99.2%, respectively.

Figure 1.

Eight-month angiographic results

Angiography at 8 months was completed for 874 lesions in 517 (51.0%) patients. In-segment and in-stent late lumen losses were (0.21±0.40) mm and (0.23±0.36) mm at angiographic follow-up, respectively. Furthermore, in-segment and in-stent binary restenosis rates were 5.7% (n=50) and 4.3% (n=38), respectively (Table 5).

Table 5

Incidence and predictors of ST

By 12 months, the cumulative ST, including ARC-defined definite, probable, and possible, was found in 16 (1.55%) patients (Table 6). Definite and probable ST was found in 12 (1.36%) patients. Acute (<24 hours), subacute (24 hours to 30 days), and late (30 days to 12 months) ST occurred in 3 (0.29%), 6 (0.58%), and 7 (0.68%) patients, respectively. ST-free survival rate at one-year clinical follow-up was 98.1% (Figure 2). Diabetes mellitus (HR 6.852 (2.091-22.453), P=0.001), small vessel lesions (HR 4.844 (1.198-19.594), P=0.027), and chronic total occlusion (CTO) lesions (HR 4.154 (1.138-15.166), P=0.031) were independent predictors of ST by Cox regression analysis (Table 7).

Table 6

Figure 2.

Table 7

Antiplatelet therapy

The frequency of dual anti-platelet therapy was 95.50% (992/1028), 95.18% (968/1017) and 70.78% (712/1006) at 30 days, 6 months, and 12 months, respectively. Aspirin utilization was 98% from 30 days to 1 year. Unplanned discontinuation of dual anti-platelet therapy occurred in 0.10% (1/1017) and 1.19% (12/1006) of patients at 6 months and 1 year, respectively (Table 8).

Table 8

DISCUSSION

In this study, we performed the first systematic evaluation of the safety and efficacy of the Firebird SES in a large cohort of Chinese patients with exclusively complex lesion anatomies. One-year clinical follow-up results showed that implantation of the Firebird stent in the current complex lesion cohort was associated with a relatively low occurrence of MACE (5.1%). The TLR at 1-year follow-up was low (3.4%), and this beneficial effect was achieved without any excess risk of cardiac death (0.6%) or non-fatal MI (1.1%). The complexity of lesions did not increase the incidence of ST (1.36%) (definite and probable by ARC definition). Diabetes, CTO, and small vessel lesions were demonstrated to be independent predictors of ST by multivariate analysis.

The emergence of DES, with associated reductions in repeat revascularization, brought enthusiasm for the percutaneous treatment of coronary artery disease. DES usage was expanded to more complex patients and lesions based on an assumption that the benefit would also extend to those group. The American College of Cardiology National Cardiovascular Data Registry reported that in 4 off-label indications (MI, in-stent restenosis, saphenous vein graft lesions, and CTO), the use of DES was associated with low short-term MACE rates, as compared with predictions based upon a previously validated model.⁹ Roy and colleagues¹⁰ also observed that the utilization of DES for off-label indications proved to be efficacious and safe when compared with a bare metal cohort matched by propensity scoring. This DES advantage was driven primarily by reductions in TLR/TVR, without associated increases in cardiac death and nonfatal MI at 12 months. These results were similar with the current studies. It should be noted, however, that both studies had enrolled limited and specific complex lesion subtypes. Other randomized trials and registries have also reported different frequencies of off-label use which were less inclusive.^11-13

Recently, Win et al¹⁴ reported that off-label use of DES was associated with a higher rate of adverse outcomes during the index admission and at 1 year. In specific, ST occurred predominantly in patients who underwent off-label DES implantation. The authors cautioned against extrapolation of the benefits of DES over bare metal stents observed in randomized clinical trials to higher-risk clinical settings that have not been critically assessed. However, in the above registry, not only complex lesions, such as multivessel disease and bifurcation lesions, but also “complex patients,” such as those ejection fraction <25% and baseline creatinine kinase-MB >3 upper limits of normal (ULN), were enrolled. A concomitant heightened MACE rate might thus be anticipated during follow-up.

To our knowledge, the present study differs from other studies in a more inclusive definition for complex lesions anatomies. In order to preclude the confounding factors of clinical factors, the “complex patients”, such as those patients with recent acute MI and severe renal dysfunction and heart failure were not enrolled in the study. In the current study, the 1029 eligible patients represented most of the frequent off-label indications in “real world” facing by Chinese cardiologists. Nonetheless, we observed a relatively low incidence of composite MACE.

There are a number of possible explanations for the difference in outcomes between the present study and prior reports. First, we employed a different definition for complex lesions. By isolating subjects with complex lesions from those with complex clinical features such as ST-elevation MI within one month, congestive heart failure with ejection fraction ≤30%, and renal failure with serum creatinine level ≥20 mg/L (177 μmol/L), we were able to specifically assess clinical outcomes attributable to lesion anatomy. Moreover, only moderate- to high-volume PCI centers (over 500/year) participated in the registry. Procedural and in-hospital mortality rates are known to vary inversely with institutional volumes.¹⁵

Although the advent of DES has represented a quantum leap in restenosis improvements over their bare metal counterparts, TLR nonetheless remains an ubiquitous and very relevant issue.¹⁶ Previous data have implicated off-label use as marker for high restenotic risk. In our study, angiographic binary restenosis was 5.7% in-segment and 4.3% in-stent, somewhat lower than observed with previous studies. TLR or clinical restenosis was 3.4% at 12 months.

In our assessment of medium-term safety of the Firebird SES in complex lesions, a relatively low incidence of stent ARC-specified ST was observed in 14 (1.55%) (definite, probable, and possible) and 12 (1.36%) patients (definite and probable). Chronologically, there were 3 (0.29 %) acute, 6 (0.58 %) sub-acute, and 7 (0.78 %) late ARC-define ST. Our data are consistent with the results of recently completed randomized controlled trials and large registries of DES in complex lesion subsets. In their 9-month observational study, Iakovou and coinvestigators¹⁷ reported 1.3%, 0.6%, and 0.7% incidences of cumulative, subacute, and late ST, respectively. Additionally, Qasim and coauthors¹⁸ reported no increased ST for off-label DES usage. They reported respective acute, subacute, and late thrombosis rates of 0.3%, 0.6%, and 1.2%. Several factors may explain the relatively low incidences of ST. First, there was good compliance with longer duration dual antiplatelet therapy. In present study, the adherences to dual anti-platelet therapy were 95.50%, 95.18%, and 70.78% at 30 days, 6 months, and 12 months, respectively. At least 98% of patients continued compliance with aspirin from 30 days to 1 year. Only 0.10% at 6 months and 1.19% at 1 year prematurely terminated dual anti-platelet therapy. There is now mounting evidence favoring prolonged dual anti-platelet therapy for DES patients.^5,19 Our findings revealed only one ST associated with premature discontinuation of anti-platelet therapy.

Premature anti-platelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction have previously been identified as predictors of thrombotic events.²⁰ To specifically address the effects on anatomic lesion complexity upon medium-term safety, patients with ST-elevation MI within one month, severe renal dysfunction, or severe left ventricular dysfunction were specifically excluded from our registry. In the current study, we found diabetes to be the strongest predictor of ST by Cox regression analysis. For anatomic features, CTO and small vessel lesions were predictors of ST. Of note, in contradistinction to prior reports, bifurcation location was not predictive of ST in our cohort.

Clinical implications

By the current registry, we utilized conservative criteria of complex coronary lesions for DES. This is the report of medium-term efficacy and safety of the Firebird SES in complex lesion subsets. This DES is widely used not only in China but also in many parts of Europe, Asia-Pacific, and South America. Our data are reassuring that the Firebird SES is associated with low incidences of cumulative and cardiac mortalities, non-fatal MI, TLR, and ST in patients with complex lesion morphologies and features. Future randomized control trials may help elucidate and confirm the safety and efficacy of this SES in various patient and lesion subtypes.

Limitations

Despite the favorable outcomes of the Firebird SES in specific patients with complex lesions observed in this study, the registry design did not include a control arm of bare metal stent. Some types of lesions such as bypass graft lesions were excluded that may affect the generalizability of the study results. Furthermore, a comparator arm of coronary artery bypass surgery may have offered interesting data. Second, continuing follow-up is needed to provide further information to evaluate the long-term safety and efficacy of Firebird SES in complex lesion subset. Third, 70.8% patients were on dual antiplatelet therapy by 12 months, substantially less than recommendations of the USA Food and Drug Administration. However, ST remained low in our study, despite of the reduced dual anti-platelet duration. Fourth, lesion severity assessment was by visual inspection, without quantitative coronary analysis or intra-vascular ultrasound examination. Last, angiographic restudy at 8 months may be too soon for DES, and certainly the angiographic follow-up rate of 51% was far short of the routinely expected 70%. The clinical implications of this relatively low angiographic rate may be limited either way.

In conclusion, the current study demonstrated the safety and efficacy of the Firebird SES in exclusively those patients with complex lesions. The results reveal a low incidence of MACE during medium-term follow-up, including a low rate of ARC-defined ST. As patients with acute ST-elevation MI within one month were excluded, these results cannot be extrapolated to that cohort. Additionally, several specific off-label angiographic and clinical characteristics including diabetes mellitus, CTO, and small vessel lesions were predictors of ST.

Appendix:

Collaborators (48) of this study are as follows: CAI Lin (Chendu Third People's Hospital, Chengdu, Sichuan 610031, China); CAO Yu (Xiangya Third Affiliated Hospital, Changsha, Hunan 410008, China); CHEN Liang-long (Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China); CONG Hong-liang (Tianjin Chest Hospital, Tianjin 300051, China); FANG Wei-yi (Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China); FU Guo-sheng (Sir Run Run Shaw Hospital, Hangzhou, Zhejiang 310020, China); GE Jun-bo (Shanghai Zhongshan Hospital Affiliated to Shanghai Fudan University, Shanghai 200030, China); HOU Yu-qing (Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China); HUANG He (Xiangtan Central Hospital, Xiangtan, Hunan 411100, China); HUANG Qian (People's Hospital of Dongguan, Dongguan, Guangdong 523018, China); HUANG Wei-jian (First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China); JIANG Hong (People's Hospital Affiliated to Wuhan University, Wuhan, Hubei 430060, China); JIN Hui-gen (Putuo District Central Hospital, Shanghai 200060, China); LI Cheng-xiang (Xijing Hospital Affiliated to Fourth Military Medical University, Xi'an, Shaanxi 710032, China); LI Guo-qing (People's Hospital of Xinjiang Wewuer Autonomous Region, Urumqi, Xinjiang 830001, China); LI Kang, HAO Heng-jian (Xuanwu Hospital of Capital Medical University, Beijing 100053, China); LI Shu-mei (Second Clinical Hospital of Jilin University, Changchun, Jilin 130041, China); LI Yan, WANG Hai-chang (Xijing Hospital Affiliated to Fourth Military Medical University, Xi'an, Shaanxi 710032, China); MA Chang-sheng (Beijing Luhe Hospital, Beijing 101149, China); MA Gen-shan (Minhang District Central Hospital, Shanghai 201100, China); MA Yi-tong (First Affiliated Hopsital of Xinjiang University, Urumqi, Xinjiang 830054, China); MIAO Zhi-lin (Shenzhou Hospital of Shenyang Medical College, Shenyang, Liaoning 110002, China); NIE Ru-qiong (Second Affiliated Hospital of Zhongshan University, Guangzhou, Guangdo 510260, China); PANG Yao-wen (Second Affiliated Hospital of China Medical University, Shenyang, Liaoning 110021, China); PU Xiao-qun (Xiangya First Affiliated Hospital, Changsha, Hunan 410008, China); QIN Yong-wen (Changhai Hospital Affiliated to Second Military Medical University, Shanghai 200433, China); QIU Jian (General Hospital of Guangzhou Military Region, Guangzhou, Guangdong 510010, China); SHEN Wei-feng, ZHANG QI (Ruijin Hospital Affiliated to Shanghai Jiao tong University, Shanghai 200025, China); SHI Bei (Zunyi Medical College Affiliated Hospital, Zunyi, Guizhou 563003, China); WANG Jian-an (Second Affiliated Hospital of Zhejiang University Medical College, Hangzhou, Zhejiang 310009, China); WANG Lei (Beijing Friendship Hospital of Capital Medical University, Beijing 100050, China); WANG Shuang (Xi'an XiDian Group Hospital, Xi'an, Shaanxi 710077, China); WANG Wei-min (Peking University People's Hospital, Beijing 100044, China); WANG Yan, WU Zong-gui (Changzheng Hospital Affiliated to Second Military Medical University, Shanghai 200003, China); WANG Yong (China-Japan Friendship Hospital, Beijing 100029, China); WU Yang (Beijing University of Traditional Chinese Medicine Subsidiary Dongfang Hospital, Beijing 100078, China); YANG Bo-song (Chinese People's Liberation Army No. 463 Hospital, Shenyang, Liaoning 110042, China); YANG Ming (Fuxing Hospital of Capital Medical University, Beijing 100038, China); YU Bo (The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China); YU Ze-hong (People's Hospital of Jiangmen, Jiangmen, Guangdong 529050, China); YUAN Yong (People's Hospital of Zhongshan, Zhongshan, Guangdong 528403, China); ZENG He-song (Tongji Hospital of Tongji Medical College of Huazhong University of Scicence & Technology, Wuhan, Hubei 430030, China); ZHANG Da-dong, Shanghai Minhang District Central Hospital, Shanghai 201100, China); ZHANG Wei-hua (Yan'an Hospital of Kunming, Kunming, Liaoning 650051, China); ZHONG Zhi-xiong (Meizhou People's Hospital, Meizhou, Guangdong 514031, China) (Note: the authors were listed by alphabet).

REFERENCES