See the corresponding editorial in this issue, pp J Neurosurg 119: , 2013 AANS, 2013

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1 See the corresponding editorial in this issue, pp J Neurosurg 119: , 2013 AANS, 2013 Risk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy Clinical article *Kelly B. Mahaney, M.D., M.S., 1 Nohra Chalouhi, M.D., 2 Stephanus Viljoen, M.D., 1 Janel Smietana, M.D., 1 David K. Kung, M.D., 1 Pascal Jabbour, M.D., 2 Ketan R. Bulsara, M.D., 3 Matthew Howard, M.D., 1 and David M. Hasan, M.D. 1 1 Department of Neurosurgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 2 Department of Neurosurgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and 3 Department of Neurosurgery, Yale Medical School, New Haven, Connecticut Object. The use of an intracranial stent requires dual antiplatelet therapy to avoid in-stent thrombosis. In this study, the authors sought to investigate whether the use of dual antiplatelet therapy is a risk factor for hemorrhagic complications in patients undergoing permanent ventriculoperitoneal (VP) shunt for hydrocephalus following aneurysmal subarachnoid hemorrhage (asah). Methods. Patients were given 325 mg acetylsalicylic acid and 600 mg clopidogrel during the coil/stent procedure, and they were maintained on dual antiplatelet therapy with acetylsalicylic acid 325 mg daily and clopidogrel 75 mg daily during hospitalization and for 6 weeks posttreatment. Patients underwent placement of VP shunt at a later time during initial hospitalization, usually between 7 and 21 days following asah. Postoperative CT scans obtained in each study patient were reviewed for hemorrhages related to placement of the VP shunt. Results. A total of 206 patients were admitted to the University of Iowa Hospitals and Clinics with asah between July 2009 and October Thirty-seven of these patients were treated with a VP shunt for persistent hydrocephalus. Twelve patients (32%) had previously undergone stent-assisted coiling and were on dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. The remaining 25 patients (68%) had undergone surgical clipping or aneurysm coiling and were not receiving antiplatelet therapy at the time of surgery. Four cases (10.8%) of new intracranial hemorrhages associated with VP shunt placement were observed. All 4 hemorrhages (33%) occurred in patients on dual antiplatelet therapy for stent-assisted coiling. No new intracranial hemorrhages were observed in patients not receiving dual antiplatelet therapy. The difference in hemorrhagic complications between the 2 groups was statistically significant (4 [33%] of 12 vs 0 of 25, p = ]). All 4 hemorrhages occurred along the tract of the ventricular catheter. Only 1 hemorrhage (1 [8.3%] of 12) was clinically significant as it resulted in occlusion of the proximal shunt catheter and required revision of the VP shunt. The patient did not suffer any permanent morbidity related to the hemorrhage. The remaining 3 hemorrhages were not clinically significant. Conclusions. This small clinical series suggests that placement of a VP shunt in patients on dual antiplatelet therapy may be associated with an increased, but low, rate of symptomatic intracranial hemorrhage. It appears that in patients who are poor candidates for open surgical clipping and have aneurysms amenable to stent-assisted coiling, the risk of symptomatic hemorrhage may be an acceptable trade-off for avoiding risks associated with discontinuation of antiplatelet therapy. The authors results are preliminary, however, and require confirmation in larger studies. ( Key Words subarachnoid hemorrhage stent ventriculoperitoneal shunt vascular disorders Aneurysmal subarachnoid hemorrhage affects up to an estimated 30,000 people in the United States annually. 11 Evolving management practices over Abbreviations used in this paper: asah = aneurysmal subarachnoid hemorrhage; EVD = external ventricular drain; VP = ventriculoperitoneal. * Drs. Mahaney and Chalouhi contributed equally to this work. J Neurosurg / Volume 119 / October 2013 the past several decades, including early surgery and the introduction of endovascular coiling, have resulted in improved outcomes in patients who survive the initial hemorrhage. However, even in patients who are treated early and do not have new postoperative neurological deficits, long-term outcome continues to be affected by comorbid conditions such as hydrocephalus. Hydrocephalus is present in up to two-thirds of patients with asah at presenta- 937

2 K. B. Mahaney et al. tion, and 10% 20% (and in some series, up to 36%) of asah patients require permanent CSF diversion with a VP shunt. 9,14,18 Ventriculoperitoneal shunting is known to be complicated by mechanical obstructions and high revision rates, though historical hemorrhagic complication rates have been low. 14 However, the evolving techniques of endovascular treatment of ruptured intracranial aneurysms and the introduction of stent technology present new challenges in managing procedural risks in this patient population. The use of intracranial stents as an adjunct to endovascular coiling has broadened the applicability of endovascular techniques in securing intracranial aneurysms. This has allowed for wide-necked aneurysms, previously not amenable to endovascular treatment, to be secured without requiring microsurgical clipping. Stent-assisted coiling is being used more frequently as a treatment for unruptured intracranial aneurysms and is gaining acceptance in the setting of SAH. 1,7 The trade-off for the wider applicability of an endovascular technique in treating ruptured intracranial aneurysms is the associated hemorrhagic and thrombotic risks attendant on the use of intracranial stents. The use of an intracranial stent requires dual antiplatelet therapy to avoid in-stent thrombosis. In patients with asah who may require CSF diversion, dual antiplatelet therapy may be associated with a higher risk of hemorrhagic complications. We have previously shown that the risk of ventriculostomy-related hemorrhage is higher in asah patients treated with stent-assisted coiling than coiling without a stent. 13 In this study, we sought to investigate whether the use of intracranial stents and dual antiplatelet therapy remains a risk factor for hemorrhagic complications in patients undergoing permanent VP shunt for hydrocephalus following asah. Methods Study Population and Procedural Technique The proposed study was approved by the University of Iowa Hospitals and Clinics Institutional Review Board. Data obtained from patients presenting to the University of Iowa Hospitals and Clinics with asah between July 2009 and October 2012 were entered into a prospective database for quality-control measures. Medical records of asah patients treated with stent-assisted coiling who underwent subsequent VP shunt placement were reviewed. Treatment of ruptured intracranial aneurysms with stentassisted coiling occurred within 48 hours of a patient s admission. Patients were given 325 mg of acetylsalicylic acid and 600 mg of clopidogrel (Plavix, Sanofi Aventis) during the coil/stent procedure. No platelet function tests were done. The EVDs were placed within 12 hours prior to starting acetylsalicylic acid and clopidogrel. All patients were maintained on dual antiplatelet therapy with acetylsalicylic acid at 325 mg daily and clopidogrel at 75 mg daily during hospitalization and for 6 weeks posttreatment. Antiplatelet therapy was not stopped in the perioperative period for VP shunt placement. Patients underwent placement of a VP shunt at a delayed time during initial hospitalization, usually between 7 and 21 days following aneurysmal hemorrhage. In all patients, an attempt to wean off the EVD was not successful and the EVD was removed within 24 hours prior to shunt placement. This was done carefully by removing the catheter very slowly. The standard technique for shunt placement was employed except that we used a monopolar device to create the scalp, postauricular, and abdominal incisions. Shunt placement was performed via the frontal approach with a bur hole at Kocher s point or via the posterior approach with a bur hole selected utilizing a posterior ventricular catheter bur hole localizer 8 and a posterior ventricular catheter guide. 10 New catheter tracks were used, with only one pass through an already existing bur hole or a new one created on the opposite side. The opposite site was selected if there was any suspicion of potential wound complication and if the EVD had been placed for longer than 10 days. Half of the shunts were placed on the opposite site via new bur holes. No EVD catheter was left and connected to the shunt. All parts of the shunt were placed after removal of the EVD. Demographics, Baseline Characteristics, and Hemorrhage Risk Factors Demographic characteristics and baseline characteristics at the time of admission were collected for the entire study population. Determination of Hemorrhagic Complications Two neurosurgeons reviewed postoperative CT scans of each study patient to search for hemorrhages associated with VP shunt placement. Hemorrhages that occurred along the tract of the ventricular catheter following placement of VP shunt were judged to be VP shunt related. Hemorrhages that occurred at a remote site from the catheter were judged not to be VP shunt related. Hemorrhages were judged to be clinically significant if they were temporally associated with a decline in neurological examination status, required further surgical intervention, and/ or caused seizures. Statistical Analysis The rates of VP shunt related hemorrhage were compared in stent-treated patients receiving antiplatelet therapy compared with patients undergoing clipping or coiling without stent assistance, utilizing the Fisher exact test. Results A total of 206 patients were admitted to the University of Iowa Hospitals and Clinics with asah between July 2009 and October Thirty-seven of these patients were treated with a VP shunt for persistent hydrocephalus. Demographic characteristics and outcomes of these patients are detailed in Table 1. Twelve patients (32%) who received a VP shunt had previously undergone treatment of ruptured intracranial aneurysm with stentassisted coiling and were on dual antiplatelet therapy with acetylsalicylic acid and clopidogrel at the time of VP shunt placement. The remaining 25 patients (68%) 938 J Neurosurg / Volume 119 / October 2013

3 Ventriculoperitoneal shunt and dual antiplatelet therapy TABLE 1: Characteristics and outcomes of the study population* Hemorrhage Age, Sex ASA & Plavix Radiographic Symptomatic Other Ventricular Catheter Location Radiographic Vasospasm Infarct 71, F yes yes yes no frontal yes no 55, M yes yes no no frontal no no 84, F yes yes no no frontal no no 46, F yes yes no no frontal no no 78, M yes no no no frontal yes no 62, F yes no no no occipital no no 65, F yes no no no occipital no no 69, F yes no no no frontal no no 75, F yes no no no frontal no no 57, F yes no no no occipital no no 60, M yes no no no frontal yes no 46, F yes no no no frontal no no 46, M yes no no no frontal no no 57, M no no no no occipital yes no 59, F no no no no occipital yes no 55, M no no no no occipital no no 67, F no no no no frontal no no 59, F no no no no frontal yes no 76, M no no no no frontal yes no 67, F no no no no frontal no no 60, M no no no no frontal no no 57, F no no no no frontal no no 77, M no no no no frontal no no 47, F no no no no frontal no no 60, F no no no no frontal yes no 21, M no no no no frontal no no 60, F no no no no frontal no no 56, M no no no no frontal no no 55, F no no no no frontal no no 54, F no no no no frontal yes no 76, F no no no no frontal no no 69, F no no no no frontal no no 70, F no no no no occipital no no 72, F no no no no frontal no no 68, F no no no no occipital no no 69, F no no no no occipital no no 58, F no no no no frontal no no * ASA = acetylsalicylic acid. Refers to infarct in the area along the tract of the ventricular catheter. had undergone surgical clipping or aneurysm coiling and were not on antiplatelet therapy at the time of surgery for VP shunt placement. Four cases (10.8%) of new intracranial hemorrhages associated with VP shunt placement were observed. All 4 hemorrhages (33%) occurred in patients on dual antiplatelet therapy for stent-assisted coiling. No new intracranial hemorrhages were observed in patients who were not on dual antiplatelet therapy. The difference in hemorrhagic J Neurosurg / Volume 119 / October 2013 complications between the 2 groups was statistically significant (4 [33%] of 12 vs 0 of 25, p = ]). All 4 hemorrhages occurred along the tract of the ventricular catheter. Figure 1 demonstrates asymptomatic postoperative hemorrhages along the ventricular catheter of a newly implanted shunt in 3 patients receiving dual antiplatelet therapy. Only 1 hemorrhage (8.3%) was clinically significant as it resulted in occlusion of the proximal shunt catheter and required revision of the VP shunt (Fig. 2). The 939

4 K. B. Mahaney et al. Fig. 1. Representative postoperative head CT scans of asymptomatic ventricular catheter associated hemorrhages following VP shunt placement in 3 different patients on dual antiplatelet therapy. patient did not incur any permanent morbidity related to the hemorrhage. The remaining 3 hemorrhages were not clinically significant. There were no hemorrhages related to change/removal of EVDs or scalp, neck, chest, or abdominal hemorrhages. No patient developed delayed complications (such as seizure) during clinical follow-up. A posterior shunt location was not associated with risk for new intracranial hemorrhage following VP shunt placement. In 9 (24%) of 37 patients who received a VP shunt, the proximal catheters were placed in a posterior location utilizing the posterior ventricular catheter bur hole localizer and guide. Three posterior shunts were placed in patients on dual antiplatelet therapy and 6 were Fig. 2. Representative postoperative head CT scan of symptomatic ventricular catheter associated hemorrhage following VP shunt placement in a patient on dual antiplatelet therapy. The hemorrhage resulted in obstruction of the ventricular catheter, requiring VP shunt revision. placed in patients not on antiplatelet therapy; none were associated with new postoperative hemorrhage. Discussion Intracranial stenting has become routine for managing large, complex, and wide-necked aneurysms at most neurovascular centers. Intracranial stents allow dense packing of aneurysms by providing a scaffold for detachable coils, and they may also provide some flow-remodeling effects through endoluminal vessel reconstruction. 4,5,19 Thromboembolic complications have been classically regarded as the major shortcoming of intracranial stenting. The rate of thromboembolic events for stent-assisted coiling ranges from 7% to 15%. 2,6 Treatment with antiplatelet therapy is therefore recommended in patients undergoing stent-assisted procedures. In the setting of asah, however, there is a reluctance to use antiplatelet agents because of the potential need for a ventriculostomy, the occurrence of an intraparenchymal hematoma, and the high likelihood of future neurosurgical procedures. For these reasons, most operators avoid the use of stents in acutely ruptured aneurysms in favor of clip ligation or other endovascular techniques that do not mandate dual antiplatelet therapy (coiling, balloon remodeling, or dual catheter technique). However, when these techniques are not feasible or appropriate, stent-assisted coiling can be performed with reasonable morbidity according to several reports. In a retrospective study of 65 patients with ruptured wide-necked aneurysms treated with stent-assisted coiling, Amenta et al. 1 reported a favorable outcome in 63.1% of patients, with major hemorrhagic complications secondary to antiplatelet therapy occurring in 7.7% and intraoperative thrombotic events in 7.7%. They concluded that stent-assisted coiling and routine treatment with antiplatelet agents was a viable option in the management of ruptured wide-necked aneurysms. Lodi et al. 15 treated 22 asah patients with stent-assisted coiling and encountered no intraoperative aneurysm rupture or ventriculostomy-associated hemorrhagic event in any patient. In a systematic review of the literature that included 339 patients, Bodily et al. 3 found clinically significant intracranial hemorrhagic complications in 8% of patients and clinically significant thromboembolic events in 6%. The authors concluded that outcomes with stenting were likely worse than those achieved without stent assis- 940 J Neurosurg / Volume 119 / October 2013

5 Ventriculoperitoneal shunt and dual antiplatelet therapy tance, but thromboembolic complications were reasonably well controlled and ventriculostomy-related hemorrhagic complications were uncommon. Recently, even flow diverters (which also require perioperative antiplatelet therapy) have been employed to treat selected patients with acutely ruptured aneurysms. 16,17,21 We have previously assessed the risk of ventriculostomy-related hemorrhagic complications in 131 asah patients and found significantly higher rates of radiographic (32% vs 14.7%, p = 0.02) and symptomatic (8% vs 0.9%, p = 0.03) hemorrhage in stent-treated patients (on dual antiplatelet therapy) versus non stent-treated patients, respectively. 13 In the current study, we assessed whether the rate of hemorrhagic complications related to VP shunt placement is also higher in stent-treated patients receiving antiplatelet therapy. We found that although the rate of radiographic hemorrhage was significantly higher in stent-treated patients, symptomatic hemorrhages were rather uncommon and did not result in any long-term morbidity. Thus, our study suggests that placement of a VP shunt may be feasible in patients undergoing stent-assisted coiling without stopping dual antiplatelet therapy. This is particularly important in intracranial stenting procedures because premature discontinuation of antiplatelet agents exposes the patient to a high risk of stent thrombosis. Data from the cardiac literature indicate that early discontinuation of clopidogrel for major surgery following coronary stent placement is associated with mortality rates as high as 26% 32%. 12,20 Likewise, in the neurosurgical literature, cessation of antiplatelet agents increased stent thrombosis by a hazard ratio of 57 and mortality by 45%. 21 These data underline the necessity to maintain optimal antiplatelet therapy following intracranial stenting procedures. Overall, the risk of major VP shunt related hemorrhages appears to be relatively low in stent-treated patients and may not justify the hazards associated with discontinuation of antiplatelet agents. However, we stress the need for further investigation of this question in larger prospective studies. In a recently published case report, Than et al. 21 discussed the perioperative management of dual antiplatelet therapy in a patient with a giant compressive basilar artery aneurysm treated with a Pipeline Embolization Device (Covidien/ev3), was placed on acetylsalicylic acid and clopidogrel, and subsequently required urgent placement of a VP shunt due to obstructive hydrocephalus. The authors discontinued acetylsalicylic acid and clopidogrel 7 days prior to shunt placement and replaced them with ibuprofen and eptifibatide. Subsequently, the ibuprofen/ eptifibatide bridge was discontinued at midnight prior to surgery, and acetylsalicylic acid and clopidogrel were restarted postoperatively. The patient had a good outcome and the authors concluded that the ibuprofen/eptifibatide bridge can be successfully used to manage patients on acetylsalicylic acid and clopidogrel requiring urgent neurosurgical procedures. Further studies are needed, however, to assess the safety of their protocol, as it is hard to draw any conclusions based on a single case. Conclusions This clinical series suggests that placement of VP J Neurosurg / Volume 119 / October 2013 shunts in patients on dual antiplatelet therapy may be associated with an increased but low rate of symptomatic intracranial hemorrhage. It appears that in patients who are poor candidates for open surgical clipping and with aneurysms amenable to stent-assisted coiling, the risk of symptomatic hemorrhage may be an acceptable trade-off for avoiding risks associated with open surgical clipping or discontinuation of antiplatelet therapy. Our study is limited by its retrospective design and small size, and our results are preliminary. Larger studies are needed to confirm our findings. Disclosure Dr. Jabbour is a consultant for ev3 and Codman Neurovascular. Author contributions to the study and manuscript preparation include the following. Conception and design: Hasan, Mahaney, Kung, Jabbour, Howard. Acquisition of data: Hasan, Mahaney, Viljoen, Smietana. Analysis and interpretation of data: Hasan, Mahaney, Chalouhi, Viljoen, Kung, Bulsara. Drafting the article: Hasan, Mahaney, Chalouhi. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Hasan. Administrative/technical/material support: Hasan, Mahaney, Chalouhi. Study supervision: Hasan. References 1. Amenta PS, Dalyai RT, Kung D, Toporowski A, Chandela S, Hasan D, et al: Stent-assisted coiling of wide-necked aneurysms in the setting of acute subarachnoid hemorrhage: experience in 65 patients. Neurosurgery 70: , Benitez RP, Silva MT, Klem J, Veznedaroglu E, Rosenwasser RH: Endovascular occlusion of wide-necked aneurysms with a new intracranial microstent (Neuroform) and detachable coils. Neurosurgery 54: , Bodily KD, Cloft HJ, Lanzino G, Fiorella DJ, White PM, Kallmes DF: Stent-assisted coiling in acutely ruptured intracranial aneurysms: a qualitative, systematic review of the literature. AJNR Am J Neuroradiol 32: , Chalouhi N, Dumont AS, Hasan D, Tjoumakaris S, Gonzalez LF, Starke RM, et al: Is packing density important in stentassisted coiling? Neurosurgery 71: , Chalouhi N, Jabbour P, Gonzalez LF, Dumont AS, Rosenwasser R, Starke RM, et al: Safety and efficacy of endovascular treatment of basilar tip aneurysms by coiling with and without stent assistance: a review of 235 cases. Neurosurgery 71: , Fiorella D, Albuquerque FC, Han P, McDougall CG: Preliminary experience using the Neuroform stent for the treatment of cerebral aneurysms. Neurosurgery 54:6 17, Gao X, Liang G, Li Z, Wei X, Hong Q: Complications and adverse events associated with Neuroform stent-assisted coiling of wide-neck intracranial aneurysms. Neurol Res 33: , Garell PC, Mirsky R, Noh MD, Loftus CM, Hitchon PW, Grady MS, et al: Posterior ventricular catheter burr-hole localizer. Technical note. J Neurosurg 89: , Hoh BL, Kleinhenz DT, Chi YY, Mocco J, Barker FG II: Incidence of ventricular shunt placement for hydrocephalus with clipping versus coiling for ruptured and unruptured cerebral aneurysms in the Nationwide Inpatient Sample database: 2002 to World Neurosurg 76: , Howard MA III, Srinivasan J, Bevering CG, Winn HR, Grady MS: A guide to placement of parietooccipital ventricular catheters. Technical note. J Neurosurg 82: , Ingall TJ, Whisnant JP, Wiebers DO, O Fallon WM: Has there 941

6 K. B. Mahaney et al. been a decline in subarachnoid hemorrhage mortality? Stroke 20: , Kałuza GL, Joseph J, Lee JR, Raizner ME, Raizner AE: Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 35: , Kung DK, Policeni BA, Capuano AW, Rossen JD, Jabbour PM, Torner JC, et al: Risk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling. Clinical article. J Neurosurg 114: , Little AS, Zabramski JM, Peterson M, Goslar PW, Wait SD, Albuquerque FC, et al: Ventriculoperitoneal shunting after aneurysmal subarachnoid hemorrhage: analysis of the indications, complications, and outcome with a focus on patients with borderline ventriculomegaly. Neurosurgery 62: , Lodi YM, Latorre JG, El-Zammar Z, Swarnkar A, Deshaies E, Fessler RD: Stent assisted coiling of the ruptured wide necked intracranial aneurysm. J Neurointerv Surg 4: , Martin AR, Cruz JP, Matouk CC, Spears J, Marotta TR: The pipeline flow-diverting stent for exclusion of ruptured intracranial aneurysms with difficult morphologies. Neurosurgery 70 (1 Suppl Operative):21 28, McAuliffe W, Wenderoth JD: Immediate and midterm results following treatment of recently ruptured intracranial aneurysms with the Pipeline embolization device. AJNR Am J Neuroradiol 33: , O Kelly CJ, Kulkarni AV, Austin PC, Urbach D, Wallace MC: Shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage: incidence, predictors, and revision rates. Clinical article. J Neurosurg 111: , Piotin M, Blanc R, Spelle L, Mounayer C, Piantino R, Schmidt PJ, et al: Stent-assisted coiling of intracranial aneurysms: clinical and angiographic results in 216 consecutive aneurysms. Stroke 41: , Sharma AK, Ajani AE, Hamwi SM, Maniar P, Lakhani SV, Waksman R, et al: Major noncardiac surgery following coronary stenting: when is it safe to operate? Catheter Cardiovasc Interv 63: , Than KD, Rohatgi P, Wilson TJ, Gregory Thompson B: Perioperative management of a neurosurgical patient requiring antiplatelet therapy. J Clin Neurosci 19: , 2012 Manuscript submitted December 28, Accepted May 23, Please include this information when citing this paper: published online June 28, 2013; DOI: / JNS Address correspondence to: David M. Hasan, M.D., Department of Neurosurgery, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA david-hasan@uiowa.edu. 942 J Neurosurg / Volume 119 / October 2013