Background Stent assisted coiling of unruptured wide necked intracranial aneurysms require antiplatelets to prevent stent thrombosis. The effect of the loading dose of antiplatelets prior to the stent coiling procedure in an unsecured wide necked ruptured intracranial aneurysm is not known.
Objective To report any potential complication associated with the use of both aspirin and clopidogrel in stent assisted coiling of ruptured wide necked intracranial aneurysms.
Methods Consecutive patients who underwent stent assisted coiling for ruptured wide necked intracranial aneurysm were enrolled from 2005 to 2009. Patients' demographics, including Hunt and Hess grade, Fisher scale, and location and size of aneurysms, were collected. Complications such as rupture of aneurysm, thromboembolic events, ventriculostomy associated or systemic hemorrhages were recorded. Additionally, a 90 day outcome measurement was obtained using the Glasgow Outcome Scale.
Results 22 patients with a mean age of 50±13 years underwent stent assisted coiling. A loading dose of clopidogrel 300 mg and aspirin 325 mg orally were given prior to stent placement. There was no intraoperative rupture of aneurysm, ventriculostomy associated hemorrhage or systemic hemorrhagic event. There were two episodes of stent thrombosis; one was an asymptomatic event which developed during the stent assisted coiling procedure and resolved spontaneously; the other was symptomatic which required intra-arterial administration of glycoprotein IIbIIIa receptor antagonist. There was no mortality and good outcome was observed in 82% of patients.
Conclusion In our series of carefully selected patients, therapeutic dual antiplatelet loading prior to stent assisted coiling of ruptured wide necked intracranial aneurysm was not associated with increased bleeding complications. However, thromboembolic events remain the main challenge. Further study is required to confirm the safety of antiplatelet loading in stent assisted ruptured intracranial aneurysm coiling.
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The challenges of stent assisted treatment of complex intracranial aneurysm have been described in previous studies. Most of the data1–9 came from experiences of using Neuroform stents (Boston Scientific Target, Fremont, California, USA) which were approved by the Food and Drug Administration in 2002 under humanitarian device exemption. The Enterprise stent (Cordis Neurovascular, Miami, Florida, USA) is a relatively new intracranial stent approved by the Food and Drug Administration in 2007 under the guideline of humanitarian device exemption for the treatment of wide necked intracranial aneurysm. The uses of these types of stents have been associated with technical challenges, including difficulties in navigation of stent, imprecise placement of stent and stent migration.1–10 The technical challenge in navigation of stent in the intracranial circulation varies from 3% to 14.2%, and the incidence of stent migration ranges from 1% to 16%. The clinical complications associated with stents include intraoperative rupture of aneurysm and immediate or delayed thromboembolic events associated with stent.1–8 10 The most common clinical complication is transient or permanent thromboembolic event related to intracranial stent, the incidence of which varies from 2% to 21%. The second most common clinical complication is intraoperative rupture of aneurysm and hemorrhage that varies from 1.5% to 15%. Most of the patients enrolled in the previous studies had unruptured wide necked aneurysms and the numbers of ruptured intracranial aneurysm patients were very small. However, two recent studies11 12 enrolled many ruptured wide necked aneurysms but the results varied. Recently, two studies13 14 deliberately evaluated the risk and benefit of stent assisted repair of ruptured intracranial aneurysms. In both studies13 14 there was no preoperative standard antiplatelet regiment using aspirin and clopidogrel for the protection of stent. However, in one,13 glycoprotein IIbIIIa receptor antagonist was administered intraoperatively prior to stent deployment.
Currently, there is no single study that has specifically used an antiplatelet regiment (both aspirin and clopidogrel) prior to the deployment of stent or evaluated the antiplatelet effect on hemorrhagic and thromboembolic complications in ruptured intracranial wide necked aneurysm. The objective of our study was to evaluate the safety, feasibility and outcome of patients who were treated with therapeutic doses of both aspirin and clopidogrel prior to stent assisted coiling of their ruptured intracranial aneurysm. Additionally, we tried to evaluate any hemorrhagic complications associated with the use of antiplatelets and placement of external ventricular drainage (EVD) catheter in our series.
Data of patients undergoing stent assisted treatment of intracranial wide necked and fusiform aneurysms were prospectively collected and maintained in a database. Twenty-two consecutive patients who underwent stent assisted coiling of an intracranial ruptured wide necked aneurysm were selected and their data were retrospectively analyzed. Institutional Review Board approval was obtained prior to the treatment and retrieval of the data. The decision regarding surgical clipping versus endovascular stent assisted treatment of the aneurysm was made on the agreement between a vascular neurosurgeon and a neuroendovascular specialist. Additionally, prior to the selection of stent assisted repair, the treating endovascular operator thoroughly evaluated the architecture of the parent artery and ruled out any perceived difficulties in navigations through the blood vessels and catheterizations of the aneurysm.
The clinical severity of subarachnoid hemorrhage was assessed using the Hunt and Hess (H&H) grade, and the radiographic grade was measured using the Fisher scale. Outcomes were predefined on the basis of radiographic and clinical criteria. Radiographic outcomes were defined as the rate of immediate occlusion (complete occlusion (100%), near complete occlusion or neck remnant (>95% but <100%) or subtotal occlusion <95%) after stent assisted coiling of the ruptured aneurysm. Clinical outcomes were measured using the Glasgow Outcome Scale (GOS). Outcome was defined as good if the obtained GOS was ≥4 at the 90 day follow-up visit.
Wide necked aneurysm was defined as having a dome to neck ratio <2 or a neck >4 mm in diameter. All patients with a ruptured aneurysm who underwent stent assisted repair were treated with both a loading dose of aspirin 325 mg and clopidogrel 300 mg at least 2 h prior to intended stent deployment. Patients were continued on both aspirin 325 mg and clopidogrel 75 mg daily for 4 weeks after the stenting procedure and thereafter on daily 325 mg aspirin alone.
An EVD was placed if indicated prior to the procedure and initiation of antithrombotic medications to prevent potential bleeding complications related to ventriculostomy insertion. We also avoided postprocedural intravenous anticoagulation in subarachnoid hemorrhage patients to prevent potential bleeding complications associated with the ventriculostomy catheter. However, standard subcutaneous anticoagulation for the prevention of deep venous thrombosis was continued.
Stent assisted coiling techniques have been described previously by us.7 15 16 Briefly, a 6 F guiding catheter (Boston Scientific Target, Fremont, California, USA) flushed with continuous heparinized saline was placed in the proximal part of the vessel of interest (internal carotid, vertebral artery) and advanced through the guiding catheter under the guidance of fluoroscope and roadmaps. The aneurysm was crossed with a microcatheter (SL 10; Boston Scientific Target) and a microwire (Synchro 14 (Boston Scientific Target) or Transcend 14 (Cordis, Miami, Florida, USA)). The microcatheter was swapped with an exchange length microwire (X-celerator 300 cm; eV3, Irvine, California, USA). Stent delivery system was prepared and advanced over the exchange length microwire as a unit and subsequently deployed across the neck of the aneurysm. Recently, we had begun to use a direct approach in which a 200 cm 0.014 compatible microwire was back loaded through the stent delivery system and the stent delivery system was then advanced as a unit through the guiding catheter. For the Enterprise stent (Cordis Neurovascular), a 14 compatible microcatheter (Prowler select 14; Boston Scientific Target) was loaded over the microwire (Synchro 14; Boston Scientific Target) which was placed on the parent artery distal to the neck of the aneurysm. Placement of the microcatheter was confirmed with a microcatheter angiogram. Baseline serum activated coagulation time was obtained, and intravenous heparin was administered after placement of the stent delivery catheter in the parent artery distal to the aneurysm and just 5–10 min prior to stent delivery to achieve an activated coagulation time of 1.5 times the baseline value. To cover the neck of the aneurysm adequately, the stent was deployed at least 4 mm proximal and 4 mm distal to the neck of the parent artery. The aneurysms in this series were catheterized by the direct approach in which the microcatheter was advanced through the interstiches of the Neuroform stent and Enterprise stent over a soft 14 compatible microwire (Synchro soft 14; Boston Scientific Target). Angiographic and clinical follow-up was planned for each patient at 3, 12, 18 and 36 months.
Patient demographics, including age, race, gender, cardiovascular risk factors, and location and size of aneurysm, were collected. A Student's t test of independent samples was performed to compare means, and either a Pearson χ2 test or Fisher's exact test was used to compare proportions. Univariate analysis was done to determine if there were clinical or patient characteristics associated with thromboembolic complications. Due to the low number of observed outcomes, multivariable analysis was not performed. All analyses were carried out using statistical software SAS V.9.1.3.
Twenty-two patients with a mean age of 50±13 years underwent successful stent assisted coiling of ruptured wide necked intracranial aneurysms using 24 intracranial stents (Neuroform 14, Enterprise 10) (figures 1 and 2). The majority of the patients were female (19/22) and basilar artery bifurcation aneurysm was present in 11 (50%) cases. A presenting H&H clinical grade I was observed in 11 patients, grade II in three patients, grade III in four patients and grade IV in four patients. A history of hypertension was present in 10/22, active smoking history in 11/22 and a history of prior intracranial aneurysm was present in one patient. In our series, antiplatelet loading with clopidogrel 300 mg and aspirin 325 mg was given at least 2 h and not more than 3 h prior to stent deployment. Fifteen patients required EVD placements—in 13 cases the EVD was placed at least 6 h before the procedure and antithrombotic loading dose while in two cases the EVD was placed after the procedure and antithrombotic loading dose, one on the same day and the other on postoperative day 2. There was no intraoperative rupture of aneurysm or hemorrhage related to ventriculostomy placement or systemic hemorrhagic events. Successful stent deployment was achieved in all cases without any significant technical difficulties.
There were two episodes of stent thrombosis. The first event was an asymptomatic non-occlusive stent thrombosis which developed during stent assisted coiling procedure in a 38-year-old woman (table 1, figure 3) with right paraophthalmic blister ruptured aneurysm (presenting H&H grade I and Fisher grade 3). In this case, early stent thrombosis occurred after multiple attempts were made to place the microcatheter into the aneurysm for suitable placement of coil. At that time it was decided to abort further attempts to catheterize the aneurysm and the microcatheter was withdrawn from the parent artery. Since the aneurysm was unsecured and the stent was non-occlusive with good antegrade flow, the operator decided to observe for 45 min to see the progression of stent thrombosis instead of administering a thrombolytic drug. The patient was given additional intravenous fluid and blood pressure was kept at the higher limit of normal. Within 20 min after withdrawal of the microcatheter, stent thrombosis began to resolve spontaneously and showed complete resolution in 45 min. The procedure was rescheduled in 6 days when successful placement of coil was achieved without any recurrent thrombosis. The patient was discharged home after 21 days with a GOS score of 5. The second event was observed on postoperative day 2 in a 46-year-old woman with H&H grade III and Fisher grade 3 who underwent stent assisted coiling of a ruptured basilar artery bifurcation aneurysm. Emergent intra-arterial administration of glycoprotein IIbIIIa receptor antagonist resulted in complete resolution of clot and symptoms. There was no mortality in our series. Good outcome was observed in 82% of patients (GOS score of 5 in 17 and GOS 4 in one) and poor outcome in 18% of patients (GOS 3 in four).
Stent assisted coiling of ruptured wide necked intracranial aneurysm patients has been included in the series of stent assisted coiling of intracranial aneurysms11 12 and the results have been conflicting. In a recent study of 40 patients with 41 acute ruptured aneurysms treated with 41 Neuroform stents, an intraoperative intravenous dose of glycoprotein IIbIIIa receptor antagonist (eptifibatide) was given intravenously during the procedure instead of oral antiplatelets prior to stent placement.13 However, a postoperative loading dose of clopidogrel and aspirin was provided. Intraoperative rupture of aneurysm was reported in 3/41 aneurysms while non-aneurysmal intracranial hemorrhage was observed in 2/40 cases. An intraoperative radiographic thromboembolic event was observed in four cases, three of which resolved after administration of eptifibatide. Ischemic stroke was observed in 5/40 cases, one immediate and four in a delayed fashioned. In another study,14 61 patients with acutely ruptured intracranial aneurysm were treated with stent assisted coiling. Most patients received intraprocedure acetylsalicylic acid. Some received heparin before stent deployment and some received heparin after stent deployment. Most received both aspirin and clopidogrel after the procedure. Technical success was observed in 72%. Intraoperative rupture of aneurysm was observed in 4/61 cases. Intraoperative thromboembolic events occurred in 9/61 cases. Mortality was observed in 20%. Good outcome was observed (GOS 5 and 4) in 69% of cases.
In comparing the results of our study with the most recent studies13 14 (table 2), reporting only ruptured aneurysms, we observed no intraoperative rupture or postoperative hemorrhages in our series. In addition, compared with our series, the thromboembolic events, including stroke, were also higher in previous series,13 14 including a study13 that utilized glycoprotein IIbIIIa receptor antagonist prior to stent deployment. These observations may be due to the differences in the pharmacological properties of antiplatelet agents used during stent assisted coiling of ruptured aneurysm.
The suspected mechanisms of intraoperative rupture of aneurysm during coiling including factors associated with the microwire, microcatheter or coils, have been described previously.7 When a ruptured aneurysm stops bleeding, we suspect that the hemostatic process has begun successfully by activation of platelets and formation of thrombus. After a few hours, the concentration of platelet in the thrombus increases, making the thrombus rich in platelets. Based on their pharmacological properties, the use of glycoprotein IIbIIIa receptor antagonists in unsecured aneurysms may promote breakdown of dihydrogen sulfate bondage between platelets, leading to the lysis of platelet rich clot/thrombus which then increases the chance of intraoperative rupture. Since both aspirin and clopidrogel have no effect on pre-existing clot or platelet rich thrombus, theoretically they will not increase the chance of aneurysm rupture or hemorrhage. However, in the event of aneurysm rupture or hemorrhage, both aspirin and clopidogrel may increase the severity of hemorrhages. We have not compared aspirin and clopidogrel with glycoprotein IIbIIIa receptor antagonists so we are unable to determine whether the combination of aspirin and clopidogrel has any clinical advantage over glycoprotein IIbIIIa receptor antagonists or vice versa.
Our study and other recently published series13 14 (table 2) revealed that the incidence of thromboembolism is higher in ruptured series than in unruptured series.7 12 15 The possible mechanism of higher rate of thromboembolism in the ruptured series, including our series, may be due to the fact that most of our patients received antiplatelet load just 2 h prior to the procedure and therefore therapeutic platelet inhibition might not have been achieved prior to stent placement. Based on a previous study,17 a loading dose of clopidogrel provides platelet inhibition of 55% in 1 h and 80% within 5 h of administration. Therefore, loading doses can be administered earlier prior to stent placement which may potentially reduce intraoperative thromboembolic events. Additionally, a bedside platelet aggregations assay can be performed for all patients just before stent placement to identify those patients who have poor platelet inhibition. For the prevention of postoperative thromboembolic events, a second loading dose of antiplatelet may be administered if a platelet inhibition assay performed postprocedure indicates poor platelet inhibition.
Our study has several limitations. Firstly, the small size of our series may be insufficient to capture the true incidence of bleeding complications of periprocedural regimens of dual antiplatelets and intraoperative intravenous heparin that we used in our cohort of patients treated for ruptured wide neck intracranial aneurysm. Secondly, in our series we did not use a balloon assisted technique in which some of these aneurysms could hypothetically have been repaired. Thirdly, the retrospective, single arm and open label design of our study may limit its external validity. However, what we report here is a pilot study examining mainly the safety, feasibility and outcome of the dual antiplatelet regimen that we used in our patients cohort.
In conclusion, in carefully selected cases, stent assisted coiling of ruptured wide necked intracranial aneurysm using preprocedural aspirin and clopidogrel loading is feasible and not associated with increased bleeding complications. Ventriculostomy related complications could be avoided if the ventriculostomy is performed at least 6 h prior to the antiplatelet loading dose. However, the thromboembolic events remain the main challenge in stent assisted coiling of ruptured intracranial wide necked aneurysm. Therefore, standard antiplatelet regimens should not be withheld prior to stent assisted coiling of carefully selected ruptured wide necked aneurysms. A larger prospective and blinded study looking at the same outcomes in a similar cohort is needed to replicate and confirm our results.
Competing interests None.
Ethics approval Institutional Review Board approval was obtained.
Provenance and peer review Not commissioned; externally peer reviewed.