Original article

Original article

Midterm outcomes of prospective, randomized, single-center
study of the Janus tacrolimus-eluting stent for treatment of
native coronary artery lesions

HAN Ya-ling, WANG Shou-li, JING Quan-min, YU Hai-bo, WANG Bin, MA Ying-yan, LUAN Bo and WANG Geng
Keywords: drug-eluting stent; acute myocardial infarction; angioplasty, transluminal; percutaneous coronary

Background Long-term efficacy and safety of tacrolimus-eluting stent (Janus) for treatment of coronary artery disease
in percutaneous coronary interventions (PCI) “real world” is uncertain. The aim of this study was to evaluate the efficacy
and safety of Janus stent for treating coronary heart disease in PCI daily practice, the safety of 4-month clopidogrel
therapy after Janus stent implantation and the feasibility for treating patients with acute myocardial infarction (AMI) for
first time.
Methods From February 20, 2006 to August 26, 2006, a total of 200 patients were enrolled and randomly assigned to
receive either Janus stent (n=100) or bare metal stent (Tecnic Carbostent, n=100). All patients were administered with
clopidogrel for 4 months and aspirin for life long after stenting.
Results Baseline clinical and angiographic characteristics were comparable between the two groups. AMI was present
in 37% of patients with Janus and 36% with Tecnic Carbostent. At an average of 246-day follow-up, major adverse
cardiac events (MACE) was 6% with the Janus stent and 15% with the Tecnic Carbostent (P=0.038). Primary events
included 1 cardiac death, 1 myocardial infarction (MI) due to subacute stent thrombosis and 13 target lesion
revascularizations (TLR) due to restenosis in patients with Tecnic Carbostent and 6 TLR due to restenosis in patients with
Janus stent. Although all patients had discontinued clopidogrel for an average of 126 days, there was no additional
thrombotic event in the two groups.
Conclusions Janus stent is efficient in reducing MACE compared with Tecnic Carbostent at an average of 8-month
follow-up. Discontinuation of clopidogrel at 4 months after PCI is safe for patients with Janus stent, including AMI patients.
Long-term efficacy of Janus stent in reducing restenosis requires further study.
rug-eluting stent (DES) has been reported to Ddramatically reduce the incidence of restenosis and target lesion revascularization (TLR), and is widely used Study population
in clinical practice in recent years. However, Between February 20, 2006 and August 26, 2006, a total controversies remain with regard to the long-term of 200 patients with symptomatic or documented efficacy and safety for the first generation DES.1 myocardial ischemia, including acute myocardial Pathological findings had indicated that polymer based DES delayed vessel healing, which might lead to late infarction (AMI), were enrolled in this prospective, severe adverse events such as in-stent thrombosis. The randomized study. Patients were considered eligible for permanent existence of non-degradable polymer coatings, enrollment if they were: fit for coronary stent which promote local vessel inflammation, is considered implantation; to be treated exclusively with one kind of as one of the leading causes reducing vessel healing. The stent, no more than 3 stents for one target vessel (or total Janus tacrolimus-eluting stent (SORIN, Italy), a novel length of stents ≤ 85 mm), and providing written DES without polymer coating, is deemed capable to informed consent. The major exclusion criteria were eliminate the adverse effects of non-degradable polymer in-stent restenosis lesion, graft lesion, not eligible for coatings of DES. Preliminary clinical outcomes from DES implantation, such as intolerant of anti-platelet Jupiter I and II studies demonstrated that Janus stent was treatment or planned to undergo surgery, and as safe as bare metal stent (BMS) and tended to reduce restenosis rate. However, the study population in Jupiter I and II comprised of only low to mid-risk patients and Department of Cardiology, Shenyang General Hospital of PLA, lesions. We conducted a prospective, randomized, Shenyang 110016, China (Han YL, Wang SL, Jing QM, Yu HB, single-center study aiming at evaluating the safety and efficacy of Janus stent for treating coronary artery disease Correspondence to: Dr. Han Ya-ling, Department of Cardiology, in “real world” clinical practice of percutaneous coronary Shenyang General Hospital of PLA, Shenyang 110016, China Chinese Medical Journal 2007;120 (7):552-556 Study protocols
Table 1. Baseline clinical characteristics
Patients were randomly assigned to receive Janus stent (n=100, Janus group) or Tecnic Carbostent (SORIN, Italy, n=100. Tecnic group) according to the computer generated randomization list. A 300-600 mg loading dose clopidogrel (Plavix, Sanofi aventis) were given for all patients at admission. Coronary angiography and stenting were performed according to the standard techniques.2 After stent implantation, all patients received dual antiplatelet therapy: aspirin 300 mg per day for the initial one month continued with 100 mg per day for life-long and clopidogrel 75 mg per day for 4 months. In patients with AMI, the antiplatelet regimen was mostly the same except clopidogrel 150 mg per day for the initial one week. Clinical follow-up was performed at 1-, 6-, 12- and CAD: coronary artery disease. AMI: acute myocardial infarction. LMWH: low 24-month and follow-up angiography was performed at 9 molecular weight heparin. PCI: percutaneous coronary intervention. NYHA: New York Heart Association. NS: not significant. End points and definitions
characteristics of the two groups were well matched The primary end point was the 12-month rate of major (Table 2). Multivessel disease was present in 7% of adverse cardiac events (MACE), defined as the composite patients in Janus group and 13% of patients in Tecnic of cardiac death, nonfatal myocardial infarction (MI) or group (All were dual vessel disease, P>0.05). TLR. The secondary end points were 9-month rate of angiographic in-stent restenosis and MACE at 24-month. MI was defined either as the development of pathological Table 2. Baseline angiographic characteristics
Q waves in at least 2 contiguous leads with or without elevated cardiac enzymes or, in the absence of pathological Q waves, as an elevation in creatinine kinase levels to greater than twice the upper limit of normal in the presence of an elevated creatinine kinase-MB level. Location of target lesions (n (%)) TLR was defined as repeat revascularization for ischemia owing to stenosis ≥ 50% of the lumen diameter anywhere within the stent or within the 5-mm borders proximal or distal to the stent. Restenosis was defined as the diameter stenosis of ≥50% of the target lesion. Statistical analysis
Categorical discrete variables were compared by the χ2 test or the Fisher exact test when appropriate. Continuous variables were presented as mean±standard deviation Small vessel lesions (≤2.75 mm) (n (%)) 12(10.6) 14(11.5) NS (SD) and were compared with the use of the Student’s t Long lesions (≥20 mm) (n (%)) 81(71.7) test. A P value <0.05 was considered statistically 99%−100% diameter stenosis (n (%)) 48(42.5) 48(39.3) NS significant. Data were analyzed using SPSS 10.0. LM: left main. LAD: left anterior descending coronary artery. LCX: left circumflex coronary artery. RCA: right coronary artery. CTO: chronic total occlusion. ACC/AHA: American College of Cardiology/American Heart Baseline clinical characteristics
The baseline clinical characteristics of the two groups
Procedural results
were well matched (Table 1). Onset of AMI within 24 There were totally 235 target lesions in 220 target vessel hours occurred in 37 patients in Janus group (including 4 of 200 observed patients underwent coronary stenting. non-ST segment elevation MI) and in 36 in Tecnic group The procedure and device-deployment success rates (including 3 non-ST segment elevation MI). The achieved 100% in the two groups. Procedural results were proportions of acute coronary syndromes (ACS) were similar for the two groups (Table 3). The maximum total 78% in Janus group and 75% in Tecnic group, stent length in one vessel was 81 mm in patients implanted with the Janus stent and 71 mm in patients implanted with Tecnic carbostent (overlapped by 3 stents). Baseline angiographic characteristics
Stents with small diameter (2.5-2.75 mm) accounted for The target lesions (113 vs 122) and target vessels (107 12.3% in Janus group and 17.0% in Tecnic group vs 113) were similar between the two groups. Lesion Table 3. Stent implantation and procedural results
of inspiritment. Because of the growing concern that delayed endothelialization after implantation of a DES may cause late stent thrombosis, prolonged dual antiplatelet therapy with clopidogrel and aspirin is currently recommended after DES implantation. Unfortunately, even with 6 months or longer period of dual antiplatelet therapy, the incidence of late thrombosis 2.5 mm diameter stent (n (%)) 11(9.0) or deadly cardiac events after DES implantation were still 2.75 mm diameter stent (n (%)) 4(3.3) higher than those after BMS implantation.3 Therefore, it 3.0 mm - 4.0 mm diameter stent (n (%)) 107(87.7) 112(83.0) NS Stent overlapping ( is important to develop a new generation of DES which might decrease the restenosis not at the expense of safety. The Janus tacrolimus-eluting stent is one of such new Distal protective device (n (%)) 0(0) 1(1) NS generation DES. As the platform of Janus stent, the Tecnic Carbostent is coated with Carbofilm to increase the biocompatibility and hemocompatibility.4,5 Phantom IV study demonstrated the efficacy and safety of Tecnic Overall clinical outcomes
Carbostent. In that study, there was no death or MI at Up to January 30, 2007, all patients were clinically 6-month clinical follow-up after Tecnic Carbostent followed up for an average of (246±48) days (ranged implantation, and the angiographic restenosis rate was 150 to 340 days). All the patients discontinued 14%.6 Of the 100 patients received the Tecnic Carbostent clopidogrel at the end of the fourth month after PCI in the present study, the stent related thrombotic events according to study protocol. The mean interval from the rate was only 1% at an average of 8-month follow-up, discontinuation of clopidogrel was (126 ± 46) days which confirms that the Tecnic Carbostent is a safe BMS (ranged 34 to 220 days). Primary events occurred in 15 platform. Having kept the structural features of the Tecnic patients in Tecnic group, including 1 cardiac death due to Carbostent, the Janus stent is coated with tacrolimus, an cardiac rupture secondary to anterior AMI, 1 AMI caused immunosuppressant, which was demonstrated to be by subacute in-stent thrombosis, 12 repeat PCI and 1 efficient in inhibiting neointima hyperplasia of porcine CABG due to in-stent restenosis, so the overall and coronary artery.7,8 Differed from the first generation DES, stent-related MACE rates were 15% and 14%, i.e. Cypher and TAXUS, Janus stent has some unique respectively. In Janus group, there were 6 primary events features. First, drugs are loaded in the embedded of repeat PCI due to in-stent restenosis, so the overall and reservoirs on the outer stent surface, which enables drugs stent-related MACE rates were all 6%. The overall releasing directly to vessel wall without being washed MACE rate was significantly lower in Janus group as away in the bloodstream. Second, there is no polymer compared with Tecnic group (6% vs 15%, P=0.038). For coating in Janus stent, which may decrease the potential the TLR and stent-related MACE, there was an obvious risks of late in-stent thrombosis caused by unabsorbable tendency of lower incidence associated with the Janus stent but not statistically significant (6% vs 14%, Jupiter I study, the first-in-man registry of Janus stent, enrolled 58 patients. Of whom, 19% were ACS (including Clinical outcomes of AMI subgroup
For the subgroup of AMI patients who underwent
6.9% of AMI). The target lesions included only 27% emergent PCI within 24 hours of symptom onset, the complex lesions of type B2/C with (11.5±5.9) mm of mean clinical follow-up was (250±46) days (ranged 154 lesion length and (70.3±14.9)% of stenosis diameter. to 323 days) in Janus group and (243±52) days (ranged The randomized, controlled Jupiter II study presented at 150 to 340 days) in Tecnic group, respectively. There was 2005 TCT showed that the total rate of MACE in the 157 no death or any thrombotic event in 37 patients in Janus patients of Janus group was 7.6%, in which 6.4% of group except 3 repeat PCI due to in-stent restenosis. In 36 MACE was related to the stent, suggesting Janus stent patients in Tecnic group, there were 4 primary end points, having better clinical effects and safety. However, ACS including 1 cardiac death, 1 MI caused by subacute accounted for only 27.6% of patients in Janus group in in-stent thrombosis and 2 repeat PCI due to in-stent Jupiter II. Furthermore, ST segment elevation MI restenosis. The incidence of death or MI was similar (STEMI) within 7 days and non-ST segment elevation MI (NSTEMI) within 3 days were all excluded in Jupiter II. patients had discontinued clopidogrel, there was no It also excluded those with complicated lesions such as additional death or thrombotic event in the two groups. ostial lesions, left main diseases, chronic total occlusions (CTO), bifurcations, lesion in small vessels (reference DISCUSSION
diameter ≤ 2.75 mm), long lesions (lesion length >20 mm) and thrombotic lesions. Complex lesions of Type Controversies about DES regarding its late clinical B2/C took only 34.9%. Because of the relatively simple outcomes were emerged and spread after the initial years lesion type, 75.9% of patients underwent successful direct Chinese Medical Journal 2007;120 (7):552-556 stenting. Compared with Jupiter I and II studies, the always confused to decide how long patients should take population in the present study included 78% of ACS dual antiplatelet therapy after DES implantation. In patients. The target lesions included many complicated Jupiter II study, about 60% patients took clopidogrel for lesions of high risk, such as left main or ostial lesions, over 6 months. Although patients in present study took thrombotic lesions, CTO, bifurcations, long lesions, small clopidogrel for 4 months and then aspirin alone, no vessel lesions with 2.5 mm in diameter. Some of the thrombosis was found after discontinuation of clopidogrel patients were highly endangered by some risk factors of for 126 days on average, preliminarily proving the coronary heart disease, for instance, diabetes, smoking feasibility and safety of this antiplatelet regimen, which and hypertension, which generally reflected the “real provides an opportunity of receiving DES for patients world” of clinical PCI daily practice. Despite of the who are intolerable of long-term dual antiplatelet therapy. higher risk for clinic and restenosis in subjects of present The relatively shorter dual antiplatelet regimen may also study, the incidence of MACE was 6% without associate with a decrease of the hemorrhage risk, adverse occurrence of death or thrombosis in Janus group during the mean 8-month follow-up. Besides, as compared with the Tecnic group, incidence of MACE was dramatically The main limitation of our study lies in that the mean follow-up period is only 8 months, which does not reach P=0.038). The rate of stent related MACE had an obvious lower tendency in Janus group but no the designed observation time and only reflects the mid-term clinical result. Because of the limited similar to that of Jupiter I and II, and further confirms the observation time, angiographic follow-up rate is low as safety and clinical efficacy of Janus stent. Different from the present study, Jupiter II did not achieve statistical differences in the total rate of MACE, which might In conclusion, for the first time we investigated the mainly due to the differences in study population. The efficacy and safety of the Janus stent, a novel DES enrolled patients in Jupiter II were mostly at lower risk without polymer coating, in “real world” PCI practice in for thrombosis. It has been reported that the effect of DES this randomized single-center study. At our mean 8-month in reducing restenosis is not superior to that of BMS for follow-up, Janus stent is efficient in reducing MACE lesions with length <15 mm and vessel diameter >2.8 compared with BMS, and is safe and efficient for treating mm.10 Moreover, Tecnic stent itself has certain AMI patients. Discontinuation of clopidogrel at 4-month antithrombotic function which may reduce the thrombosis related events in the control group in Jupiter II, in which late lumen lost was only 0.64 mm, and the incidence of in-stent restenosis was 14.8% in patients implanted with Tecnic stent. This was probably the reason for Jupiter II 1. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, to come to the conclusion that the total incidences of O’Shaughnessy C, et al. Sirolimus-eluting stents versus MACE and stent related MACE in Janus group were not standard stents in patients with stenosis in a native coronary significantly lower than those in Tecnic group. artery. N Engl J Med 2003; 349: 1315-1323. 2. Han YL, Wang G, Jing QM, Wang SL, Wang ZL, Wang DM, Up to now, the safety of DES implantation in primary et al. Percutaneous coronary intervention in acute coronary PCI is uncertain. The randomized Typhoon trial showed syndrome: single center experience from 4670 patients. Natl that sirolimus eluting stent for treatment of STEMI was efficient in reducing MACE and TLR compared with 3. Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, BMS, but not beneficial for death, MI or in-stent Hunziker P, Mueller C, et al. Late clinical events after thrombosis.11 In the present study, more than a third of clopidogrel discontinuation may limit the benefit of study population were those with STEMI or NSTEMI drug-eluting stents. J Am Coll Cardiol 2006; 48: 2584-2591. undergoing emergent PCI within 24 hours of symptom 4. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, onset, which were excluded in Jupiter I and II study. For Perin M, et al. A randomized comparison of a 37 AMI patients (including 33 STEMI) in Janus group, no sirolimus-eluting stent with standard stent for coronary acute, subacute or late thrombosis occurred at an average revascularization. N Engl J Med 2002; 346: 1773-1780. 8-month follow-up, suggesting Janus stent is safe in 5. Sousa JE, Costa MA, Abizaid AC, Rensing BJ, Abizaid AS, Tanajura LF, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year It was reported that incomplete endothelialization even angiographic and intravascular ultrasound follow-up. appeared 1-2 years after implantation of Cypher or TAXUS in some cases.12 The reports of very late in-stent 6. Danzi GB, Capuano C, Sesana M, Baglini R, Bartorelli AL, thrombosis (>1 year) after DES implantation were also Trabattoni D, et al. Six-month clinical and angiographic not rare.13 Long-term dual antiplatelet therapy may outcomes of the tecnic carbostentTM coronary system: the reduce the risk of thrombosis, but simultaneously phantom IV study. J In vasasive Cardiol 2004; 11: 641-644. accompanies the increased adverse effects, such as 7. Kollum M, Farb A, Schreiber R, Terfera K, Arab A, Geist A, et hemorrhage, and the financial burden. Therefore, it is al. Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis. Catheter Cardiovasc Interv 11. Spaulding C, Henry P, Teiger E, Beatt K, Bramucci E, Carre D, et al. Sirolimus-eluting versus uncoated stents in acute 8. Scheller B, Grandt A, Wnendt S, Lorenz G, Bohm M, myocardial infarction. N Engl J Med 2006; 355: 1093-1104. Nickenig G. Comparative study of tacrolimus and paclitaxel 12. Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, stent coating in the porcine coronary model. Z Kardiol 2005; Minamiquchi H, et al. Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings. J Am Coll Trabattoni D, Fabbiocchi F, Montorsi P, Martini SD, Calligaris G, et al. Synergy of passive coating and targeted 13. Takahashi S, Kaneda H, Tanaka S, Miyashita Y, Shiono T, drug delivery: the tacrolimus-eluting Janus Carbostent. J Taketani Y, et al. Late angiographic stent thrombosis after sirolimus-eluting stent implantation. Circ J 2007; 71: 226-228. 10. Pache J, Dibra A, Mehili J, Dirschinger J, Schomig A, Kastrati A. Drug-eluting stents compared with thin-strut bare stents for the reduction of restenosis: a prospective, randomized trial. Edited by WANG Mou-yue and SHEN Xi-bin

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