Original Paper Received: July 23, 2013 Accepted: December 9, 2013 Published online: April 8, 2014
Eur Neurol 2014;71:319–325 DOI: 10.1159/000357866
Argatroban for Preventing Occlusion and Restenosis after Extracranial Artery Stenting Lulu Zhou a Dezhi Liu b Yun Li a, b Wusheng Zhu a, b Wen Sun a, b Yongkun Li a, b Yunyun Xiong a, b Zhaoyao Chen c Qizhang Wang a, d Qiankun Cai a, b Zhaolu Wang a, b Xiaomeng Wang a, b Wenshan Sun a, b Liang Ge a, b Minmin Ma a, b Min Li a, b Hua Li a, b Xinying Fan a, b Qin Yin a, b Gelin Xu a, b George Liu e Xiaobing Fan a, b Xinfeng Liu a, b
Departments of Neurology at a Jinling Hospital, Southern Medical University, b Jinling Hospital, Nanjing University School of Medicine, c The Affiliated Hospital of Nanjing University of TCM, Nanjing, and d Shenzhen Shajing People’s Hospital, Guangzhou Medical University, Guangzhou, and e Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, PR China
Abstract Background/Aims: Restenosis following extracranial artery stenting is a limitation that affects long-term outcomes. Effective and satisfying pharmacological strategies in preventing restenosis have not been established. This study aimed to evaluate whether argatroban, a direct thrombin inhibitor, could reduce the risk of in-stent restenosis after extracranial artery stenting. Methods: One hundred and fourteen patients hospitalized between August 2010 and August 2011 were enrolled. Patients were randomly assigned to argatroban (n = 58) and blank control groups (n = 56). The patients in the argatroban arm were treated with 10 mg of intravenous argatroban twice daily 2 days before and 3 days after the stenting procedures. Patients were followed for 12 months after the procedure. During follow-up, restenosis and target revascularization were analyzed. Recurrent cere-
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0319$39.50/0 E-Mail [email protected] www.karger.com/ene
brovascular and cardiovascular events and deaths were also compared between the groups. Results: One patient in the stenting group withdrew immediately after the procedure due to unsuccessful stenting. Restenosis occurred in 4 patients (7.4%) in the argatroban group and in 11 patients (21.6%) in the control group during the 6- to 9-month angiographic follow-up period (p = 0.032). Nine months after the procedures, argatroban-treated patients had a trend towards a lower incidence of target revascularization compared with the controls (5.4 vs. 13.7%, p = 0.188). No major bleeding events or other adverse events occurred in the argatroban group. Conclusion: This pilot clinical trial is the first that uses argatroban to prevent restenosis in ischemic cerebrovascular disease, and suggests that intravenous administration of argatroban is effective and safe in preventing restenosis after extracranial artery stenting. Larger randomized controlled clinical trials are warranted. © 2014 S. Karger AG, Basel
L.Z. and D.L. contributed equally to this work. This study was registered at Clinicaltrials.gov (No. 01163604).
Xinfeng Liu, MD Department of Neurology, Jinling Hospital, Southern Medical University 305# East Zhongshan Road Nanjing 210002, Jiangsu Province (PR China) E-Mail xfliu2 @ vip.163.com
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Key Words Argatroban · Restenosis · Thrombin · Extracranial artery stenting
Ischemic cerebrovascular disease is an important cause of death and long-term disability worldwide. Endovascular treatment has played an increasingly important role in the treatment of ischemic stroke caused by cerebrocervical artery stenosis. However, some major complications including perioperative distal embolism, thrombogenesis, and restenosis are associated with extracranial artery stenting. In-stent restenosis (ISR) is a critical issue and occurs in 6–32.4% of patients with cervicocranial stenting within 1 year after the procedure [1–5]. Although several antiplatelet and antithrombin agents have been tested in the prevention of these complications, the effects are very limited, and extra risk of bleeding has been observed in some patients [6–8]. Thrombin is a major protease in the coagulation cascade and platelet aggregation and one of the most extensively studied enzymes [9]. Thrombin also activates numerous cells involved in ISR, including monocytes, mast cells, endothelial cells, and vascular smooth muscle cells (VSMCs) [10, 11]. Thus, thrombin may play a key role in the formation of ISR. In addition to the role as a direct inhibitor of thrombin, argatroban can inhibit the thrombin-induced DNA synthesis in VSMCs and latent matrix metalloproteinase-2 activation [11]. It has been demonstrated that argatroban could reduce restenosis after coronary balloon angioplasty [12]. This knowledge justified a rationale for the use of argatroban in patients undergoing stenting procedures. The current pilot randomized study aims to evaluate the feasibility of argatroban in preventing ISR in extracranial stenting patients.
Methods Study Population The present study was a single-center, open-label, prospective, randomized, controlled pilot study. Enrollment of participants began in August 2010 and was completed in August 2011. The local ethics committee approved the study, and written informed consent was obtained from all recruited patients. The study was also approved by the Review Board of the Jinling Hospital, Nanjing, PR China, and registered at www.clinicaltrials.org (No. 01163604). This was a pilot trial with no previous randomized clinical trials on which to base power calculations. Inclusion criteria were listed as follows: patients were eligible for enrollment if they had symptomatic atheromatous extracranial artery stenosis, and stenting was considered for stenosis ≥50%. Extracranial artery was subdivided into two groups: (1) the extracranial carotid artery (C1), and (2) the extracranial vertebral artery (V1–3). Symptomatic stenosis was defined as: (1) stenosis of extracranial carotid artery or extracranial vertebral artery on digital subtraction angiography (DSA), magnetic reso-
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nance angiography (MRA) or computed tomography angiography (CTA), and (2) acute ischemic lesions on magnetic resonance imaging, and corresponding to the patients’ neurological deficits within the vascular territory of the stenosed artery. Lesions must be covered completely by a stent with a reference vessel diameter of ≥2 mm on DSA. Exclusion criteria included (1) age >80 or 0.75 or Cohen k >0.7 indicated good agreement. The angiographic follow-up outcomes were performed by on-treatment analyses. Moreover, clinical follow-up outcomes were performed by intention-to-treat analyses.
Statistical Analysis All statistical analyses were performed using SPSS Statistics 19.0 software, with a two-sided significant level of p = 0.05. Since this trial was a pilot study, sample sizes were determined without a priori power calculations before beginning of the trial, but based on a sufficient number to estimate the treatment effect size. Patient characteristics and information on the intervention procedure were compared in the active and control groups. Continuous vari-
Baseline Clinical and Angiographic Characteristics A total of 114 patients were prospectively enrolled in the study between August 2010 and August 2011 (fig. 1). Fifty-eight patients were randomly assigned to the arg-
Argatroban in the Prevention of Extracranial Artery Stenting
Eur Neurol 2014;71:319–325 DOI: 10.1159/000357866
Results
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tients returned for follow-up DSA, MRA or CTA, and clinical outcomes were recorded. Those in whom follow-up angiography, MRA or CTA showed definite imagine evidence of symptomatic restenosis underwent another interventional therapy. The primary end point was ISR defined as >50% stenosis in extracranial artery detected on follow-up angiography. Stenosis was evaluated according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method for extracranial artery [14]. Major secondary clinical end points were as follows: (1) the rate of target vessel revascularization at 6–9 months after the procedure, and (2) death, recurrent stroke, and transient ischemic attack (TIA), as well as cardiovascular events. Target vessel revascularization was defined as repeat stenting or balloon angioplasty treatment of the extracranial artery performed for either ischemic neurologic symptoms and a stenosis of at least 50% of the luminal diameter or a stenosis of at least 80% without neurologic symptoms. A cardiovascular event was defined as any of the following adjudicated events: myocardial infarction, congestive heart failure, or cardiac bypass graft surgery.
0.9
0.8 Argatroban Control
0.7
0.6
0
2
4 6 8 Months after angioplasty
10
12
Fig. 2. Kaplan-Meier distribution of patients without clinical events in the intention-to-treat analysis. The groups were compared by the log-rank test (p = 0.584).
Table 1. Clinical and neuroimaging characteristics at baseline
Argatroban group (n = 58) Males Age, years Arterial hypertension Diabetes mellitus Hypercholesterolemia History of smoking History of stroke Coronary heart disease Target lesion characteristics Ulceration Eccentricity Irregular contour Lesion length, mm Target lesion location Extracranial carotid artery Extracranial vertebral artery Stent type Express SD Blue Precise Wallstent Stent length, mm Stent diameter, mm
Control group (n = 56)
51 (87.9) 65±9 42 (72.4) 13 (22.4) 12 (20.7) 30 (51.7) 19 (32.8) 14 (24.1)
51 (91.1) 63±9 47 (83.9) 19 (33.9) 10 (17.9) 23 (41.1) 14 (25.0) 11 (19.6)
0.585 0.287 0.137 0.171 0.702 0.254 0.361 0.562
30 (51.7) 34 (58.6) 18 (31.0) 11.38±5.24
27 (48.2) 38 (67.9) 14 (25.0) 10.40±4.64
0.708 0.307 0.473 0.293
36 (62.1)
33 (58.9)
0.732
22 (37.9)
23 (41.1)
0.732
17 (30.4) 18 (35.3) 0.681 7 (12.5) 6 (11.8) 0.907 31 (55.4) 30 (58.8) 0.718 3 (5.4) 2 (3.9) 1.000 28.07±11.87 28.14±11.46 0.973 6.53±2.19 6.83±2.31 0.471
Values are means ± SD or n (%).
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p value
Eur Neurol 2014;71:319–325 DOI: 10.1159/000357866
Angiographic Follow-Up Outcome The 6- to 9-month angiographic results were available for 107 of 114 patients (93.9%). The analysis of the secondary angiographic end points was repeated on a per lesion basis. Restenosis rates after binary angiography were 7.4% (4/56) in the argatroban group and 21.6% (11/51) in the control group, and had a significant difference (p = 0.032). Restenosis rates of extracranial carotid artery were 5.7% (2/35) in the argatroban group and 13.8% (4/29) in the control group (p = 0.397), and for extracranial vertebral artery, the rates were 9.5% (2/21) and 31.8% (7/22), respectively (p = 0.132). Cumulative clinical event-free survivals at 12 months are shown in figure 2. The average late increase in the stenosis rate among patients receiving argatroban was lower than that in the control group (p = 0.125) (fig. 3). Target revascularization rates were 5.4% (3/56) in the argatroban group and 13.7% (7/51) in the control group, respectively (p = 0.188). Perioperative Complications and Clinical Follow-Up Outcomes No bleeding events occurred in either group in the follow-up during the perioperative period. One-year clinical follow-up was obtained in all but 3 patients. The incidences of clinical end points at 1 year after stenting are summarized in table 2, and have no significant difference. All patients received their dual antiplatelet regimen, they
Zhou et al.
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Proportion of patients without clinical events
1.0
atroban and 56 to the control groups. Two patients in the argatroban group were excluded from data analysis: 1 failed the stenting procedure and 1 had no follow-up angiography. Five patients in the control group were excluded from data analysis, 3 had no follow-up angiography, and 2 were lost to clinical follow-up. The baseline clinical and angiographic characteristics of the patients were summarized in table 1. There was no significant difference in characteristics between the argatroban group and the control group. The evaluation of stenosis in this study reached good agreement. The ICC values for minimal luminal diameter before, immediately after, and 9 months after angioplasty were 0.98, 0.96, and 0.96, respectively, and all were >0.75. The values of minimal luminal diameter were expressed as means. The interrater reliability (Cohen k) for ISR was 1.00, which is considered to represent substantial agreement. Cohen k for ulceration, eccentricity, and irregular contour was calculated as 0.95, 0.93, and 0.97, respectively. The disputes of these nominal variables were resolved by discussion.
Mean stenosis rate (%)
20
the procedure. Both patients were in the control group. No other major complications occurred during the procedure in either group. Within the 1-year follow-up, 1 patient of the control group was readmitted to the hospital because of hemiplegia and hematemesis occurring 6 months after the first angiography. Although we found out that acute cerebral infarction and gastrointestinal bleeding were the causes, the patient died 15 days after treatment start. Overall, recurrent stroke or TIA occurred in 5 patients in the argatroban group, and 6 patients in the control group at the 1-year follow-up.
p = 0.125
Argatroban Control
15 10 5 0
Postoperative stenosis rate
Late increase in stenosis rate
Fig. 3. There was no significant difference between the two groups in the postoperative stenosis rate (p = 0.780). The average late increase in the stenosis rate among patients receiving argatroban was lower than that in the control group (9.5 vs. 15.9%, p = 0.125). Bars denote mean ± SD.
Discussion
took dual antiplatelet drugs for just 3 months and continued to take a single antiplatelet drug. There were no imbalances in terms of duration of single or dual antiplatelet therapy in the two groups. Within 3 days after stenting, 2 patients developed an acute occlusion in the treated location after stent implantation during hospitalization, which resulted in an extensive cerebral infarction, with progressive hemiplegia after
This is the first randomized trial to show that periprocedural argatroban treatment is useful in reducing restenosis after extracranial artery stenting. Data from our study provide evidence that argatroban treatment prevents restenosis without an increase in severe adverse effects. Cumulative clinical event-free survival between the two groups was associated without significant difference. Argatroban was associated with decrease in the rate of restenosis and the target revascularization as compared with the control group. The rate of cerebral events, cardiovascular events and death at 3 days and 1 year after angioplasty did not differ between the two groups, respectively. Several preclinical studies suggest a relationship between the early thrombotic response and the later development of restenosis [7, 15–17]. In our study, a clear beneficial effect of argatroban on early platelet aggregation and thrombus formation was indicated by the prevention of acute ischemic events after stenting. Early in-stent thrombosis occurred in 3 patients of the control group after the procedure. Consequently, antithrombin and antithrombotic are important in the prevention of restenosis. To date, this medication failed to produce a significant reduction of coronary restenosis in most studies involved with a variety of drugs aimed at reducing early thrombotic events [18–20]. In several of these restenosis trials, it was argued that medication was initiated too late for influencing early thrombotic events after the procedures. Considering that the thrombin receptor will appear a few minutes after endothelial injury in stenting or balloon expansion [21], and 3–5 days after angioplasty has been demonstrated to be the peak of the proliferation of VSMCs [22], intravenous infusion of argatroban is performed 2 days before angioplasty and continued for the following 3 days.
Argatroban in the Prevention of Extracranial Artery Stenting
Eur Neurol 2014;71:319–325 DOI: 10.1159/000357866
Table 2. Clinical and neuroimaging outcomes at follow-up
Argatroban Control group group (n = 51) (n = 56) Neuroimaging outcomes Reference luminal diameter, mm Minimal luminal diameter, mm Before angioplasty Immediately after angioplasty 9 months after angioplasty Target revascularization Clinical outcomes Death Recurrent stroke Cardiovascular events TIA Cerebrovascular events Extracranial carotid artery Extracranial vertebral artery
p value
5.36±1.20
5.18±1.26 0.449
1.29±0.80 5.04±1.19 4.50±1.43 3 (5.4)
1.12±0.87 4.93±1.25 4.04±1.67 7 (13.7)
0.295 0.630 0.131 0.188 0.447 0.346 1.000 1.000
0 (0) 1 (1.8) 1 (1.8) 4 (7.1)
1 (2.0) 3 (5.9) 0 (0) 3 (5.9)
4 (7.1) 1 (1.8)
4 (7.8) 1.000 2 (3.9) 0.604
Values are means ± SD or n (%).
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25
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clinical events. Clinical events in this study are defined as death, recurrent stroke, and TIA, as well as cardiovascular events, compared to stroke (fatal or disabling stroke), death or procedural myocardial infarction. This therapy could represent an advance in the prevention of early thrombogenesis and restenosis; however, in this trial, argatroban treatment failed to alter the longterm clinical outcomes. Several trials have obtained similar results comparable with our study [20, 35]. It still remains unclear why argatroban treatment does not provide a similar benefit in the prevention of restenosis. The results may be explained by the fact that most restenosis patients are clinically asymptomatic and the number of patients is limited. Further investigation with more patients is necessary to determine whether the large decrease in restenosis rates observed with argatroban can be translated to an analogous long-term outcome. In contrast to the control group, the argatroban group had no significant side effects regarding bleeding events. The patient who died from gastrointestinal bleeding 6 months after the first angiography belonged to the control group. In the present study, argatroban administration did not increase the risk of bleeding. It is worthy to mention some limitations of our study. First, it should be noted that our clinical trial did not avoid the heterogeneity of the stenosis location. Second, a 5-day use of argatroban during the perioperative may play a limited role in anticoagulation for later thrombus formation. Therapy duration may be too short for reducing restenosis. Studies to evaluate the optimal duration and monitoring effect of this agent are needed. Third, the present study was performed in a single center with a limited number of patients. Further multicenter, doubleblind, randomized study with more patients is necessary. Argatroban was safe and effective in preventing restenosis after extracranial artery stenting in this trial. Therefore, it may provide a feasible therapeutic option for preventing ISR after extracranial artery stenting. Acknowledgements The authors thank Miss Ying Lin for her assistance in patient follow-up. This study was supported by the Natural Science Foundation of China (NSFC No. 30870847 to X.L., NSFC No. 81000501 to D.L., and NSFC No. 30870848 to G.X.).
Disclosure Statement The authors have no conflicts of interest to disclose.
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Argatroban may prevent restenosis by inhibiting thrombin generation, platelet aggregation, and adhesion. Response-to-injury processes during the perioperative period have been confirmed to be implicated with restenosis formation [23, 24]. Thrombin provides an important target to control thrombogenesis [25], platelet aggregation and adhesion [9]. It also plays important roles in fibrin deposition, VSMCs migration and proliferation, some growth factor modulations and leukocyte transmigration, all of which participate in the process of restenosis [26]. Their inhibition during the perioperative period may obtain unexpected results. Another possible explanation for our findings might be the powerful anticoagulant and anti-inflammatory effects of argatroban. Argatroban can also inhibit soluble and postclotting thrombin which binds to fibrin or blood clot, and is better than heparin and other direct thrombin inhibitors [27]. Furthermore, other advantages include antiplatelet effect by reducing the thrombin-mediated activation of platelets [28], the protective effect of endothelial cells [29], and downregulation of various inflammatory and thrombotic cytokines [30]. Of interest is that our data are virtually in complete agreement with previously published data on the effect of argatroban in patients undergoing coronary balloon angioplasty [12]. Itoh et al. [12] reported that the intracoronary local delivery of argatroban, in addition to a 4-hour intravenous infusion, significantly reduced the rate of restenosis in a population of patients undergoing coronary balloon angioplasty. Although it has been confirmed that argatroban is useful in extracranial artery in this trial, the effect of the argatroban treatment was not shown in extracranial vertebral arteries or carotid artery with significant difference, respectively. The small sample size may limit a satisfactory effect for independent arteries. Restenosis occurred in 14.0% of extracranial artery lesions, which is higher than in most of the last major multicenter carotid artery stenting trials (5.7–11.1%) [31–33]. There may be two reasons that explain this result. First, the overall incidence of restenosis within the current study included that of extracranial carotid artery and extracranial vertebral artery, compared with only extracranial carotid artery in the other trials. Second, in this study, ISR was defined as >50% of stenosis with NASCET criteria in extracranial artery detected on follow-up angiography; however, in other studies, ISR was defined as a reduction in the diameter of the target artery of at least 70% [31, 32]. There is a higher incidence of clinical events within the current study than in some prior studies [32, 34], which might be explained by a difference in the definition of
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Argatroban in the Prevention of Extracranial Artery Stenting
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Eur Neurol 2014;71:319–325 DOI: 10.1159/000357866
Argatroban for Preventing Occlusion and Restenosis after Extracranial Artery Stenting Lulu Zhou a Dezhi Liu b Yun Li a, b Wusheng Zhu a, b Wen Sun a, b Yongkun Li a, b Yunyun Xiong a, b Zhaoyao Chen c Qizhang Wang a, d Qiankun Cai a, b Zhaolu Wang a, b Xiaomeng Wang a, b Wenshan Sun a, b Liang Ge a, b Minmin Ma a, b Min Li a, b Hua Li a, b Xinying Fan a, b Qin Yin a, b Gelin Xu a, b George Liu e Xiaobing Fan a, b Xinfeng Liu a, b
Departments of Neurology at a Jinling Hospital, Southern Medical University, b Jinling Hospital, Nanjing University School of Medicine, c The Affiliated Hospital of Nanjing University of TCM, Nanjing, and d Shenzhen Shajing People’s Hospital, Guangzhou Medical University, Guangzhou, and e Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing, PR China
Abstract Background/Aims: Restenosis following extracranial artery stenting is a limitation that affects long-term outcomes. Effective and satisfying pharmacological strategies in preventing restenosis have not been established. This study aimed to evaluate whether argatroban, a direct thrombin inhibitor, could reduce the risk of in-stent restenosis after extracranial artery stenting. Methods: One hundred and fourteen patients hospitalized between August 2010 and August 2011 were enrolled. Patients were randomly assigned to argatroban (n = 58) and blank control groups (n = 56). The patients in the argatroban arm were treated with 10 mg of intravenous argatroban twice daily 2 days before and 3 days after the stenting procedures. Patients were followed for 12 months after the procedure. During follow-up, restenosis and target revascularization were analyzed. Recurrent cere-
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0319$39.50/0 E-Mail [email protected] www.karger.com/ene
brovascular and cardiovascular events and deaths were also compared between the groups. Results: One patient in the stenting group withdrew immediately after the procedure due to unsuccessful stenting. Restenosis occurred in 4 patients (7.4%) in the argatroban group and in 11 patients (21.6%) in the control group during the 6- to 9-month angiographic follow-up period (p = 0.032). Nine months after the procedures, argatroban-treated patients had a trend towards a lower incidence of target revascularization compared with the controls (5.4 vs. 13.7%, p = 0.188). No major bleeding events or other adverse events occurred in the argatroban group. Conclusion: This pilot clinical trial is the first that uses argatroban to prevent restenosis in ischemic cerebrovascular disease, and suggests that intravenous administration of argatroban is effective and safe in preventing restenosis after extracranial artery stenting. Larger randomized controlled clinical trials are warranted. © 2014 S. Karger AG, Basel
L.Z. and D.L. contributed equally to this work. This study was registered at Clinicaltrials.gov (No. 01163604).
Xinfeng Liu, MD Department of Neurology, Jinling Hospital, Southern Medical University 305# East Zhongshan Road Nanjing 210002, Jiangsu Province (PR China) E-Mail xfliu2 @ vip.163.com
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Key Words Argatroban · Restenosis · Thrombin · Extracranial artery stenting
Ischemic cerebrovascular disease is an important cause of death and long-term disability worldwide. Endovascular treatment has played an increasingly important role in the treatment of ischemic stroke caused by cerebrocervical artery stenosis. However, some major complications including perioperative distal embolism, thrombogenesis, and restenosis are associated with extracranial artery stenting. In-stent restenosis (ISR) is a critical issue and occurs in 6–32.4% of patients with cervicocranial stenting within 1 year after the procedure [1–5]. Although several antiplatelet and antithrombin agents have been tested in the prevention of these complications, the effects are very limited, and extra risk of bleeding has been observed in some patients [6–8]. Thrombin is a major protease in the coagulation cascade and platelet aggregation and one of the most extensively studied enzymes [9]. Thrombin also activates numerous cells involved in ISR, including monocytes, mast cells, endothelial cells, and vascular smooth muscle cells (VSMCs) [10, 11]. Thus, thrombin may play a key role in the formation of ISR. In addition to the role as a direct inhibitor of thrombin, argatroban can inhibit the thrombin-induced DNA synthesis in VSMCs and latent matrix metalloproteinase-2 activation [11]. It has been demonstrated that argatroban could reduce restenosis after coronary balloon angioplasty [12]. This knowledge justified a rationale for the use of argatroban in patients undergoing stenting procedures. The current pilot randomized study aims to evaluate the feasibility of argatroban in preventing ISR in extracranial stenting patients.
Methods Study Population The present study was a single-center, open-label, prospective, randomized, controlled pilot study. Enrollment of participants began in August 2010 and was completed in August 2011. The local ethics committee approved the study, and written informed consent was obtained from all recruited patients. The study was also approved by the Review Board of the Jinling Hospital, Nanjing, PR China, and registered at www.clinicaltrials.org (No. 01163604). This was a pilot trial with no previous randomized clinical trials on which to base power calculations. Inclusion criteria were listed as follows: patients were eligible for enrollment if they had symptomatic atheromatous extracranial artery stenosis, and stenting was considered for stenosis ≥50%. Extracranial artery was subdivided into two groups: (1) the extracranial carotid artery (C1), and (2) the extracranial vertebral artery (V1–3). Symptomatic stenosis was defined as: (1) stenosis of extracranial carotid artery or extracranial vertebral artery on digital subtraction angiography (DSA), magnetic reso-
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nance angiography (MRA) or computed tomography angiography (CTA), and (2) acute ischemic lesions on magnetic resonance imaging, and corresponding to the patients’ neurological deficits within the vascular territory of the stenosed artery. Lesions must be covered completely by a stent with a reference vessel diameter of ≥2 mm on DSA. Exclusion criteria included (1) age >80 or 0.75 or Cohen k >0.7 indicated good agreement. The angiographic follow-up outcomes were performed by on-treatment analyses. Moreover, clinical follow-up outcomes were performed by intention-to-treat analyses.
Statistical Analysis All statistical analyses were performed using SPSS Statistics 19.0 software, with a two-sided significant level of p = 0.05. Since this trial was a pilot study, sample sizes were determined without a priori power calculations before beginning of the trial, but based on a sufficient number to estimate the treatment effect size. Patient characteristics and information on the intervention procedure were compared in the active and control groups. Continuous vari-
Baseline Clinical and Angiographic Characteristics A total of 114 patients were prospectively enrolled in the study between August 2010 and August 2011 (fig. 1). Fifty-eight patients were randomly assigned to the arg-
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Results
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tients returned for follow-up DSA, MRA or CTA, and clinical outcomes were recorded. Those in whom follow-up angiography, MRA or CTA showed definite imagine evidence of symptomatic restenosis underwent another interventional therapy. The primary end point was ISR defined as >50% stenosis in extracranial artery detected on follow-up angiography. Stenosis was evaluated according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method for extracranial artery [14]. Major secondary clinical end points were as follows: (1) the rate of target vessel revascularization at 6–9 months after the procedure, and (2) death, recurrent stroke, and transient ischemic attack (TIA), as well as cardiovascular events. Target vessel revascularization was defined as repeat stenting or balloon angioplasty treatment of the extracranial artery performed for either ischemic neurologic symptoms and a stenosis of at least 50% of the luminal diameter or a stenosis of at least 80% without neurologic symptoms. A cardiovascular event was defined as any of the following adjudicated events: myocardial infarction, congestive heart failure, or cardiac bypass graft surgery.
0.9
0.8 Argatroban Control
0.7
0.6
0
2
4 6 8 Months after angioplasty
10
12
Fig. 2. Kaplan-Meier distribution of patients without clinical events in the intention-to-treat analysis. The groups were compared by the log-rank test (p = 0.584).
Table 1. Clinical and neuroimaging characteristics at baseline
Argatroban group (n = 58) Males Age, years Arterial hypertension Diabetes mellitus Hypercholesterolemia History of smoking History of stroke Coronary heart disease Target lesion characteristics Ulceration Eccentricity Irregular contour Lesion length, mm Target lesion location Extracranial carotid artery Extracranial vertebral artery Stent type Express SD Blue Precise Wallstent Stent length, mm Stent diameter, mm
Control group (n = 56)
51 (87.9) 65±9 42 (72.4) 13 (22.4) 12 (20.7) 30 (51.7) 19 (32.8) 14 (24.1)
51 (91.1) 63±9 47 (83.9) 19 (33.9) 10 (17.9) 23 (41.1) 14 (25.0) 11 (19.6)
0.585 0.287 0.137 0.171 0.702 0.254 0.361 0.562
30 (51.7) 34 (58.6) 18 (31.0) 11.38±5.24
27 (48.2) 38 (67.9) 14 (25.0) 10.40±4.64
0.708 0.307 0.473 0.293
36 (62.1)
33 (58.9)
0.732
22 (37.9)
23 (41.1)
0.732
17 (30.4) 18 (35.3) 0.681 7 (12.5) 6 (11.8) 0.907 31 (55.4) 30 (58.8) 0.718 3 (5.4) 2 (3.9) 1.000 28.07±11.87 28.14±11.46 0.973 6.53±2.19 6.83±2.31 0.471
Values are means ± SD or n (%).
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p value
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Angiographic Follow-Up Outcome The 6- to 9-month angiographic results were available for 107 of 114 patients (93.9%). The analysis of the secondary angiographic end points was repeated on a per lesion basis. Restenosis rates after binary angiography were 7.4% (4/56) in the argatroban group and 21.6% (11/51) in the control group, and had a significant difference (p = 0.032). Restenosis rates of extracranial carotid artery were 5.7% (2/35) in the argatroban group and 13.8% (4/29) in the control group (p = 0.397), and for extracranial vertebral artery, the rates were 9.5% (2/21) and 31.8% (7/22), respectively (p = 0.132). Cumulative clinical event-free survivals at 12 months are shown in figure 2. The average late increase in the stenosis rate among patients receiving argatroban was lower than that in the control group (p = 0.125) (fig. 3). Target revascularization rates were 5.4% (3/56) in the argatroban group and 13.7% (7/51) in the control group, respectively (p = 0.188). Perioperative Complications and Clinical Follow-Up Outcomes No bleeding events occurred in either group in the follow-up during the perioperative period. One-year clinical follow-up was obtained in all but 3 patients. The incidences of clinical end points at 1 year after stenting are summarized in table 2, and have no significant difference. All patients received their dual antiplatelet regimen, they
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Proportion of patients without clinical events
1.0
atroban and 56 to the control groups. Two patients in the argatroban group were excluded from data analysis: 1 failed the stenting procedure and 1 had no follow-up angiography. Five patients in the control group were excluded from data analysis, 3 had no follow-up angiography, and 2 were lost to clinical follow-up. The baseline clinical and angiographic characteristics of the patients were summarized in table 1. There was no significant difference in characteristics between the argatroban group and the control group. The evaluation of stenosis in this study reached good agreement. The ICC values for minimal luminal diameter before, immediately after, and 9 months after angioplasty were 0.98, 0.96, and 0.96, respectively, and all were >0.75. The values of minimal luminal diameter were expressed as means. The interrater reliability (Cohen k) for ISR was 1.00, which is considered to represent substantial agreement. Cohen k for ulceration, eccentricity, and irregular contour was calculated as 0.95, 0.93, and 0.97, respectively. The disputes of these nominal variables were resolved by discussion.
Mean stenosis rate (%)
20
the procedure. Both patients were in the control group. No other major complications occurred during the procedure in either group. Within the 1-year follow-up, 1 patient of the control group was readmitted to the hospital because of hemiplegia and hematemesis occurring 6 months after the first angiography. Although we found out that acute cerebral infarction and gastrointestinal bleeding were the causes, the patient died 15 days after treatment start. Overall, recurrent stroke or TIA occurred in 5 patients in the argatroban group, and 6 patients in the control group at the 1-year follow-up.
p = 0.125
Argatroban Control
15 10 5 0
Postoperative stenosis rate
Late increase in stenosis rate
Fig. 3. There was no significant difference between the two groups in the postoperative stenosis rate (p = 0.780). The average late increase in the stenosis rate among patients receiving argatroban was lower than that in the control group (9.5 vs. 15.9%, p = 0.125). Bars denote mean ± SD.
Discussion
took dual antiplatelet drugs for just 3 months and continued to take a single antiplatelet drug. There were no imbalances in terms of duration of single or dual antiplatelet therapy in the two groups. Within 3 days after stenting, 2 patients developed an acute occlusion in the treated location after stent implantation during hospitalization, which resulted in an extensive cerebral infarction, with progressive hemiplegia after
This is the first randomized trial to show that periprocedural argatroban treatment is useful in reducing restenosis after extracranial artery stenting. Data from our study provide evidence that argatroban treatment prevents restenosis without an increase in severe adverse effects. Cumulative clinical event-free survival between the two groups was associated without significant difference. Argatroban was associated with decrease in the rate of restenosis and the target revascularization as compared with the control group. The rate of cerebral events, cardiovascular events and death at 3 days and 1 year after angioplasty did not differ between the two groups, respectively. Several preclinical studies suggest a relationship between the early thrombotic response and the later development of restenosis [7, 15–17]. In our study, a clear beneficial effect of argatroban on early platelet aggregation and thrombus formation was indicated by the prevention of acute ischemic events after stenting. Early in-stent thrombosis occurred in 3 patients of the control group after the procedure. Consequently, antithrombin and antithrombotic are important in the prevention of restenosis. To date, this medication failed to produce a significant reduction of coronary restenosis in most studies involved with a variety of drugs aimed at reducing early thrombotic events [18–20]. In several of these restenosis trials, it was argued that medication was initiated too late for influencing early thrombotic events after the procedures. Considering that the thrombin receptor will appear a few minutes after endothelial injury in stenting or balloon expansion [21], and 3–5 days after angioplasty has been demonstrated to be the peak of the proliferation of VSMCs [22], intravenous infusion of argatroban is performed 2 days before angioplasty and continued for the following 3 days.
Argatroban in the Prevention of Extracranial Artery Stenting
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Table 2. Clinical and neuroimaging outcomes at follow-up
Argatroban Control group group (n = 51) (n = 56) Neuroimaging outcomes Reference luminal diameter, mm Minimal luminal diameter, mm Before angioplasty Immediately after angioplasty 9 months after angioplasty Target revascularization Clinical outcomes Death Recurrent stroke Cardiovascular events TIA Cerebrovascular events Extracranial carotid artery Extracranial vertebral artery
p value
5.36±1.20
5.18±1.26 0.449
1.29±0.80 5.04±1.19 4.50±1.43 3 (5.4)
1.12±0.87 4.93±1.25 4.04±1.67 7 (13.7)
0.295 0.630 0.131 0.188 0.447 0.346 1.000 1.000
0 (0) 1 (1.8) 1 (1.8) 4 (7.1)
1 (2.0) 3 (5.9) 0 (0) 3 (5.9)
4 (7.1) 1 (1.8)
4 (7.8) 1.000 2 (3.9) 0.604
Values are means ± SD or n (%).
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25
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clinical events. Clinical events in this study are defined as death, recurrent stroke, and TIA, as well as cardiovascular events, compared to stroke (fatal or disabling stroke), death or procedural myocardial infarction. This therapy could represent an advance in the prevention of early thrombogenesis and restenosis; however, in this trial, argatroban treatment failed to alter the longterm clinical outcomes. Several trials have obtained similar results comparable with our study [20, 35]. It still remains unclear why argatroban treatment does not provide a similar benefit in the prevention of restenosis. The results may be explained by the fact that most restenosis patients are clinically asymptomatic and the number of patients is limited. Further investigation with more patients is necessary to determine whether the large decrease in restenosis rates observed with argatroban can be translated to an analogous long-term outcome. In contrast to the control group, the argatroban group had no significant side effects regarding bleeding events. The patient who died from gastrointestinal bleeding 6 months after the first angiography belonged to the control group. In the present study, argatroban administration did not increase the risk of bleeding. It is worthy to mention some limitations of our study. First, it should be noted that our clinical trial did not avoid the heterogeneity of the stenosis location. Second, a 5-day use of argatroban during the perioperative may play a limited role in anticoagulation for later thrombus formation. Therapy duration may be too short for reducing restenosis. Studies to evaluate the optimal duration and monitoring effect of this agent are needed. Third, the present study was performed in a single center with a limited number of patients. Further multicenter, doubleblind, randomized study with more patients is necessary. Argatroban was safe and effective in preventing restenosis after extracranial artery stenting in this trial. Therefore, it may provide a feasible therapeutic option for preventing ISR after extracranial artery stenting. Acknowledgements The authors thank Miss Ying Lin for her assistance in patient follow-up. This study was supported by the Natural Science Foundation of China (NSFC No. 30870847 to X.L., NSFC No. 81000501 to D.L., and NSFC No. 30870848 to G.X.).
Disclosure Statement The authors have no conflicts of interest to disclose.
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Argatroban may prevent restenosis by inhibiting thrombin generation, platelet aggregation, and adhesion. Response-to-injury processes during the perioperative period have been confirmed to be implicated with restenosis formation [23, 24]. Thrombin provides an important target to control thrombogenesis [25], platelet aggregation and adhesion [9]. It also plays important roles in fibrin deposition, VSMCs migration and proliferation, some growth factor modulations and leukocyte transmigration, all of which participate in the process of restenosis [26]. Their inhibition during the perioperative period may obtain unexpected results. Another possible explanation for our findings might be the powerful anticoagulant and anti-inflammatory effects of argatroban. Argatroban can also inhibit soluble and postclotting thrombin which binds to fibrin or blood clot, and is better than heparin and other direct thrombin inhibitors [27]. Furthermore, other advantages include antiplatelet effect by reducing the thrombin-mediated activation of platelets [28], the protective effect of endothelial cells [29], and downregulation of various inflammatory and thrombotic cytokines [30]. Of interest is that our data are virtually in complete agreement with previously published data on the effect of argatroban in patients undergoing coronary balloon angioplasty [12]. Itoh et al. [12] reported that the intracoronary local delivery of argatroban, in addition to a 4-hour intravenous infusion, significantly reduced the rate of restenosis in a population of patients undergoing coronary balloon angioplasty. Although it has been confirmed that argatroban is useful in extracranial artery in this trial, the effect of the argatroban treatment was not shown in extracranial vertebral arteries or carotid artery with significant difference, respectively. The small sample size may limit a satisfactory effect for independent arteries. Restenosis occurred in 14.0% of extracranial artery lesions, which is higher than in most of the last major multicenter carotid artery stenting trials (5.7–11.1%) [31–33]. There may be two reasons that explain this result. First, the overall incidence of restenosis within the current study included that of extracranial carotid artery and extracranial vertebral artery, compared with only extracranial carotid artery in the other trials. Second, in this study, ISR was defined as >50% of stenosis with NASCET criteria in extracranial artery detected on follow-up angiography; however, in other studies, ISR was defined as a reduction in the diameter of the target artery of at least 70% [31, 32]. There is a higher incidence of clinical events within the current study than in some prior studies [32, 34], which might be explained by a difference in the definition of
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Argatroban in the Prevention of Extracranial Artery Stenting
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