A Randomized Controlled Trial On Effects Of Argartroban On Restenosis And Clinical Events After Cerebral Vascular Stenting

Part I Argatroban for preventing occlusion and restenosis after intracranial and extracranial artery stentingObjective:This study aimed to evaluate whether argatroban, a direct thrombin inhibitor, could reduce risk of in-stent restenosis (ISR) after intracranial and extracranial artery stenting.Methods:A single-center, prospective, randomized, controlled pilot study was designed. Patients who met the criteria of performing stenting were admitted to our hospital from August2010to December2011. The inclusion criteria were listed as follows:For extracranial artery lesion, stenting was considered for symptomatic stenosis≥50%or asymptomatic stenosis≥70%; Regarding to intracranial artery lesion, stenting was considered for symptomatic stenosis≥70%in patients not responsive to intensive medical therapy. The exclusion criteria included (1) more than80years old or less than18years old;(2) severe bleeding tendency,(3) recent intracranial, extracranial hemorrhage or active peptic ulcer within3months;(4) hypersensitivity to contrast agent and test drugs;(5) malignant hypertension;(6) severe hepatic or cardiac disorders,(7) infectious disorders.Two days before the scheduled stenting, patients were randomized to receive argatroban or not. After enrolling, patients were assigned to the argatroban group or the control group by means of block randomization method (4numbers as a block). In the argatroban group, an intravenous infusion of10mg of argatroban in250ml saline for3hours was administered twice daily2days before and3days after intervention. Base data was collected before intervention, including abdominal perimeter,hypertension of history, diabetes of history, smoking of history. Coagulation function including activeated partial thromboplastin time (aPTT) should be monitoring2hs after the start of the Argatroban infusion. aPTT should be measured when the start of administration or6hs after dose changes for cases with liver injury and bleeding risk. Once aPTT value is over3times of the baseline value, the drug should be discontinued to prevent the occurrence of bleeding events. All patients received aspirin (100mg daily) and clopidogrel (75mg daily) for3days before intervention as periprocedural antiplatelet therapy. After the intervention,75mg of clopidogrel once daily was prescribed for at least three months, while100mg of aspirin once daily for life long. During the treatment, patients should avoid the use of other drugs that affect coagulation. In addition, the groups were also similar with respect to other concomitant medication, including statins, antidiabetic agents, and antihypertensive agents. Safety was evaluated as bleeding events, anaphylaxis, and liver dysfunction in perioperative period. Bleeding events include intracerebral hemorrhage, retroperitoneal hemorrhage, and alimentary tract hemorrhage. Once symptoms occur, the treatment should be discontinued immediately, and the patients would be given symptomatic treatment. Most patients underwent standardized cerebrovascular angiography by experienced neurointerventionalists at admission and repeated cerebrovascular angiography the6-to9-month follow-up. The angiograms were analyzed by2neurointerventional professionals. A successful intervention was defined as at least half diminution in stenosis post-procedure than pre-procedure for intracranial artery. For extracranial artery it was defined as achievement of a residual stenosis less than<30%. All statistical analyses were performed using SPSS Statistics19.0software, with a two-sided significance level of P=0.05. The baseline characteristics were performed by intention-to-treat analyses. Moreover, angiographic follow-up outcomes were performed by on-treatment-analyses. Continuous variables were expressed as (means±SD) or M50(Q25, Q75) and analyzed using the unpaired t-test or Mann-Whitney test, and nominal variables were analyzed using Fisher exact or the chi-square test. Uni-and multivariate Cox proportional hazards models were employed to assess the association between one and multiple variables and the event of interest. Factors related to the development of ISR were evaluated by univariate Cox regression analysis (P<0.10) in an exploratory manner, and multivariate analysis was conducted by argatroban treatment, stenosis location, history of stroke and history of smoke in addition to the extracted factors. In patients with multilesion interventions, only the most severe lesion was selected for the analysis.Results:A total of140patients were prospectively enrolled in the study between August2010and December2011. Seventy patients were randomly assigned to the argatroban, and70to the control groups. Four patients in the argatroban group were excluded from angiography data analysis:1failed stenting procedure,2without follow-up angiography, and1without complete clinical follow-up data. Five patients in the control group were excluded from angiography data analysis;3without follow-up angiography, and2lost to clinical follow-up. Overall, a total of9patients (Argatroban group4cases, control group5cases) were excluded from the clinical or angiography follow-up and eventually there were131cases enrolled in the trial with full follow-up base (argatroban group66cases, control group65cases). There was no significant difference on baseline clinical and angiographic characteristics between the argatroban group and the control group. No bleeding events occurred in either group during follow-up period. No one experience aPTT value that over3times of the baseline value. Restenosis rates after binary angiography were7.6%(5/66) in the argatroban group and24.6%(16/65) in the control group, with a significant difference (x2=7.064, P=0.008). We found that argatroban treatment (adjusted Hazard Ratio[HR]=3.021;95%confidence interval [CI]:1.098-8.292; P=0.032) and stenosis location (adjusted HR=2.762;95%CI:1.065-7.159; P=0.037) were independent risk predictors for ISR.Conclusions:Intravenous infusion of argatroban2days before angioplasty and continued for the following3days is effective and safe in preventing restenosis after intracranial and extracranial artery stentings. Part Ⅱ Long term clinical results after intracranial and extracranial artery stenting with argatrobanObjective:To study long term clinical results after intracranial and extracranial artery stenting with argatroban.Methods:Patients was included from August2010to December2011in the Nanjing Stroke Registry Projects.140cases from the study of Part I were followed up for clinical results. Patients who underwent successful interventional procedures were then followed-up at the hospital’s outpatient clinic every3months after the procedure for clinical events. The primary clinical endpoints were as follows:(1) death, any stroke including ischemic or hemorrhagic and transient ischemic attack(TIA) within30days after procedure,(2) the rate of target vessel revascularization (TVR) and ipsilateral cerebral ischemic events after procedure. The secondary clinical endpoints were death in30days after procedure, any stroke including ischemic or hemorrhagic, and TIA, as well as disease of cardiovascular system. All statistical analyses were performed using SPSS Statistics19.0software, with a two-sided significance level of P=0.05. The results of clinical follow-up were analysed by intention to treat, including all patients in the two groups. Nominal variables were analyzed using Fisher exact or the chi-square test. The Kaplan-Meier method was used to compare and calculate adverse event rates between the two groups. The chi-square test was used to compare the incidence of thromboembolic events, hemorrhagic events, and deaths, and a composite of these events in the two groups, and the Kaplan-Meier method was used to compare the composite of events. Uni-and multivariate Cox proportional hazards models were employed to assess the association between one and multiple variables and the event of interest. Factors related to the development of ISR were evaluated by univariate Cox regression analysis (P<0.10) in an exploratory manner, and multivariate analysis was conducted by argatroban treatment, stenosis location, history of stroke and history of smoke in addition to the extracted factors.Results:The primary clinical endpoints:(1)Recurrent stroke or TIA occurred in3patients in the control group (x2=3.066,P=0.245) at30-day follow-up.(2) Clinical restenosis(including TVR and ipsilateral cerebral ischemic events) occurred in3patients (4.3%) in the argatroban group, and10patients (14.3%) in the control group after procedure(x2=5.227, P=0.022). Cumulative primary clinical events-free survivals are significant difference between the two groups(x2=5.227, P=0.022). Participants who received argatroban treatment were at greater risk for clinical restenosis after the periprocedural period up to the end of follow-up than were those who did not receive argatroban (HR=3.946;95%CI:1.101-14.149; P=0.035). Participants who had restenosis or occlusion within6-9months were at greater risk for clinical restenosis after the periprocedural period up to the end of follow-up than were those who did not have restenosis (HR=18.049;95%CI:5.574-58.440; P<0.001). The secondly clinical events:any clinical event rates,11.4%in argatroban group (8/70), and12.9%in the control group (9/70), was no significant difference between the two groups (x2=0.197, P=0.657). Within two-year follow-up, one patient of the control group was readmitted to the hospital with hemiplegia and hematemesis6months after the first angiography. We found that ISR (HR=20.682;95%CI:4.633-92.369; P<0.001), stenosis location (HR=3.246;95%CI:1.030-7.628; P=0.011) and history of diabetes (HR=4.036;95%CI:1.020-7.777; P=0.026) were independent risk predictors for clinical events at two-year follow-up.Conclusions:Argatroban may be able to improve the long-term efficacy of cerebral vascular stent by inhibiting in-stent restenosis. Further multi-center, double-blind, randomized study with more patients is necessary to confirm the results.