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We thank the respondents for providing their case experience and allowing further discussion of this important topic. We would first like to draw attention to specific points in the described case, before discussing some of the more general issues raised.
The respondents report one of many scenarios in which it may be undesirable to use dual antiplatelet therapy in the elective treatment of intracranial aneurysms with flow diverters. In this case, a 47-year-old woman with an 11 mm left ophthalmic aneurysm harbours a significant aspirin allergy. A single Pipeline Shield device under cover of ticagrelor was used to treat the aneurysm. The patient was well at discharge on postoperative day three but then developed symptomatic stent thrombosis on day 6. We draw attention to three points:
1) The respondents state that the stent achieved “perfect wall apposition improved with intra-stent balloon angioplasty.” Setting aside the impossibility of improving “perfect wall apposition” with angioplasty, this does allude to the increasingly understood importance of flow diverter wall apposition.  However, digital subtraction angiography assess stent apposition poorly.  The use of angioplasty suggests that there may have been some initial concern. Moreover, angioplasty itself may contribute to thrombosis if it promotes activation of the extrinsic clotting pathway by disrupting the endothelial layer. The phosphocholine “Shield” layer reduces thrombosis and platelet...
1) The respondents state that the stent achieved “perfect wall apposition improved with intra-stent balloon angioplasty.” Setting aside the impossibility of improving “perfect wall apposition” with angioplasty, this does allude to the increasingly understood importance of flow diverter wall apposition.  However, digital subtraction angiography assess stent apposition poorly.  The use of angioplasty suggests that there may have been some initial concern. Moreover, angioplasty itself may contribute to thrombosis if it promotes activation of the extrinsic clotting pathway by disrupting the endothelial layer. The phosphocholine “Shield” layer reduces thrombosis and platelet aggregation via retarding activation of clotting factor XII at the stent surface(intrinsic pathway). It will exert no effect on the extrinsic pathway should it be activated.
2) The respondents do not mention if platelet response to ticagrelor was tested. This is not a criticism, as it is common to use new generation P2Y12 antagonists without testing their efficacy. However, it is also essential to understand ticagrelor resistance is reported in up to 3% of the population.  More recently we have experienced stent occlusions using the aspirin only technique in patients who were subsequently found to be aspirin non-responders. Given the loss of redundancy inherent in a single antiplatelet therapy (SAPT) technique, anti-platelet response testing should be reconsidered.
3) The timing of the symptomatic stent occlusion is noteworthy as it occurred three days post-discharge from hospital. This is somewhat unusual, as typically SAPT stent occlusions occur more acutely. Ticagerol’s shorter half-life means its effect will be subtherapeutic if discontinued for three days. Therefore, given the suspicious timing of the patient's stent occlusion, issues with patient compliance should be considered.
The use of the Pipeline Shield with aspirin only is a technique reserved for extreme circumstances. In aneurysmal SAH patients who cannot be treated successfully without the use of a stent and in whom antiplatelet therapy is undesirable or contraindicated, this technique may be appropriate. This has been stated in the original manuscript and is apparent in the description of the aneurysms treated. Our study reported an asymptomatic thromboembolic complication rate of 14.3% and a symptomatic rate of 7.1%.  Given the complex and extremely challenging nature of these cases, a symptomatic thromboembolic complication rate of 7.1% may be acceptable. The respondents point out that the combined rate is 21.4%. Any complications are too many, however, bear in mind that the thromboembolic complication rate in CLARITY was 12.5%.  Given the latter patient population underwent routine aneurysm coiling and the former represents patients without conventional treatment options this difference seems acceptable. Moreover, the symptomatic thromboembolic complication rate in the SAPT study is not very different from that reported in either ASPIRe or IntrePED. [5,6]
We believe that the addition of the phosphocholine "Shield" surface modification may allow greater flexibility in the use of antiplatelet therapy. It is increasingly clear that antiplatelet therapy is central to complications with flow diverting stents. Recent meta-analysis demonstrates that a hypo-response to DAPT increases the risk of thromboembolic complications and that a hyper-response increases the risk of haemorrhagic complications.  In the setting of acute aneurysm rupture, antiplatelet therapy is even more critical. The use of DAPT in such patients has been shown to increase the risks of haemorrhagic complications dramatically.  Therefore, any technology that may reduce our reliance on antiplatelet therapy should be fully explored.
The use of SAPT in complex ruptured aneurysms has nuanced advantages that may not be apparent to all readers. Many operators choose to delay treatment of ruptured aneurysms requiring a flow diverter to avoid dual antiplatelet therapy (DAPT) acutely. The mean time from subarachnoid haemorrhage (SAH) to aneurysm treatment in our study was one day. In comparison to 7 days in the meta-analysis reported by Cagnazzo et al.  This is particularly important to bear in mind when comparing retrospective studies as patients who re-ruptured before treatment will be excluded from analysis, however, undoubtedly represent treatment failure. This point is highlighted in a recent report by ten Brick and colleagues.  In this study, 44 patients with aneurysmal subarachnoid haemorrhage were treated with flow diverting stents on DAPT in five European centres. A range of flow diverters were used. However, none had the "Shield" surface modification. Aneurysm and patients characteristics were similar to the SAPT series we reported. Aneurysms were treated acutely (mean of three days post-SAH), although not as early as in the SAPT study.  Procedure-related complications occurred in 44%. Permanent neurological deficit due to procedure-related complications occurred in 27%. Perhaps of most interest to this discussion, post-procedure intracranial bleeding occurred in 22.7% including five aneurysm re-bleeds, two intraparenchymal haemorrhages not related to ventriculostomy, two ventricular shunt-related haemorrhages and one extra-axial haemorrhage. With extracranial haemorrhagic complications reported in another 9.1%.  In the SAPT series, two aneurysm re-bleeds occurred with one patient making a full recovery. The other patient, who was already a poor WFNS grade SAH never regained consciousness from the initial ictus. Both patients were being treated with postoperative heparin infusion at the time of aneurysm re-rupture, a practice which was subsequently abandoned as described in the original manuscript. In spite of similar patient and aneurysm characteristics, the DAPT case series reported good clinical outcomes in 45.5% compared to 64.3% in the SAPT series. Procedure-related mortality occurred in 11.4% and 7.1% of the DAPT and SAPT series, respectively.
Finally, it is essential to clarify the use of the term single antiplatelet therapy (SAPT). We are forced to take considerable responsibility for any misuse of this term. One should not consider the use of only one agent as the goal of this work. Instead, the goal is to offer patients with complex ruptured aneurysms, treatment using flow diverting (or other) stents with as little suppression of platelet function as is possible to avoid thromboembolic complications. The term "single antiplatelet therapy" has begun to appear in the literature, regarding the use of agents such as ticagrelor and prasugrel. Such terminology is literally correct; however, it misses the real goal of this work. As compared to P2Y12 antagonists, aspirin has a much less pronounced effect on platelet function and naturally, less haemorrhagic complication risk.  In most patients, agents such as ticagrelor and prasugrel likely suppress platelet function to such a degree that they make the addition of aspirin mostly redundant. [12,13]
We agree that further investigation of this technique is required, as stated in the original article. However, we think a randomised control trial would be inappropriate at this stage. It is somewhat facile to call for a randomised control trial to solve all medical dilemmas. It is safe to say that no treatment option is established for patients harbouring such complex ruptured aneurysms and therefore deciding on a control group would be somewhat arbitrary.
Furthermore, it is likely to be challenging to detect a significant difference in clinical outcomes given the uncertain prognosis of such patients independent of how their aneurysms are secured. Therefore, the number of patients that would need to be randomised likely exceeds 1000. We have elected to take a different approach and will study the Pipeline Shield SAPT technique in a multicentre, single-arm, prospective study. We hope that the first patients will be enrolled before this letter is published. The study will begin in Australia; however, it is planned to expand to other countries, and we encourage experienced and skilled centres such as yours to be a part of this investigation.
Thank you once again for an engaging discussion. Warm regards,
1 Rouchaud A, Ramana C, Brinjikji W, et al. Wall Apposition Is a Key Factor for Aneurysm Occlusion after Flow Diversion: A Histologic Evaluation in 41 Rabbits. Am J Neuroradiol 2016;37:2087–91. doi:10.3174/ajnr.a4848
2 Warlo EM, Arnesen H, Seljeflot I. A brief review on resistance to P2Y12 receptor antagonism in coronary artery disease. Thrombosis J 2019;17:11. doi:10.1186/s12959-019-0197-5
3 Manning NW, Cheung A, Phillips TJ, et al. Pipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience. Journal of neurointerventional surgery 2019;11:694–8. doi:10.1136/neurintsurg-2018-014363
4 Pierot L, Cognard C, Anxionnat R, et al. Ruptured intracranial aneurysms: factors affecting the rate and outcome of endovascular treatment complications in a series of 782 patients (CLARITY study). Radiology 2010;256:916–23. doi:10.1148/radiol.10092209
5 Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm Study of Pipeline in an Observational Registry (ASPIRe). Interventional Neurology 2016;5:89–99. doi:10.1159/000446503
6 Kallmes D, Hanel R, Lopes D, et al. International retrospective study of the pipeline embolization device: a multicenter aneurysm treatment study. American Journal of Neuroradiology 2015;36:108–15. doi:10.3174/ajnr.a4111
7 Ajadi E, Kabir S, Cook A, et al. Predictive value of platelet reactivity unit (PRU) value for thrombotic and hemorrhagic events during flow diversion procedures: a meta-analysis. J Neurointerv Surg 2019;11:1123. doi:10.1136/neurintsurg-2019-014765
8 Hudson JS, Prout BS, Nagahama Y, et al. External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual Antiplatelet Therapy: A Retrospective Cohort Study. Neurosurgery Published Online First: 2018. doi:10.1093/neuros/nyy127
9 Cagnazzo F, di Carlo D, Cappucci M, et al. Acutely Ruptured Intracranial Aneurysms Treated with Flow-Diverter Stents: A Systematic Review and Meta-Analysis. American Journal of Neuroradiology 2018;39:1669–75. doi:10.3174/ajnr.a5730
10 ten Brinck MF, Jäger M, de Vries J, et al. Flow diversion treatment for acutely ruptured aneurysms. J Neurointerv Surg 2019;:neurintsurg-2019-015077. doi:10.1136/neurintsurg-2019-015077
11 Gresele P. Antiplatelet agents in clinical practice and their haemorrhagic risk. Blood Transfus Trasfusione Del Sangue 2013;11:349–56. doi:10.2450/2013.0248-12
12 KIRKBY N, LEADER P, CHAN M, et al. Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 2011;9:2103–5. doi:10.1111/j.1538-7836.2011.04453.x
13 Warner TD, Nylander S, Whatling C. Anti‐platelet therapy: cyclo‐oxygenase inhibition and the use of aspirin with particular regard to dual anti‐platelet therapy. Brit J Clin Pharmaco 2011;72:619–33. doi:10.1111/j.1365-2125.2011.03943.x
We read with interest the case series by Manning’s et al. using a surface modified flow-diverter stent (Pipeline Flex with Shield Technology, Medtronic Neurovascular, Irvine, California, USA). In this retrospective series, 14 ruptured intracranial aneurysms have been treated in the acute phase after Sub-Arachnoid Hemorrhage (SAH) with the Pipeline shield device under a Single Anti-Platelet Therapy (SAPT). The article concluded the PED-Shield to be safe to use in the acute treatment of ruptured intracranial aneurysms with SAPT.
However, in this small series, the authors reported one case of total stent occlusion and two cases of platelet aggregation noted on the PED-Shield device requiring to switch from single to dual antiplatelet treatment. Considering those three patients, thrombotic complications have been observed in 21.4 % of cases (3/14) in the acute period. Furthermore, in two cases (14.3 %), the authors reported rebleeding of the culprit aneurysm leading to patient death, pointing out the fact that flow-diverter devices may not immediately prevent the risk of aneurysm rerupture.
Anti-thrombogenic coating might have an added value in case of very specific aneurysms cases requiring the placement of a stent in the acute phase after rupture. Those specific cases are mainly dissecting or blister aneurysms for which endovascular or even surgical approach are difficult and carry a high risk of morbi-mortality. In case of endovascular treatment, rece...
Anti-thrombogenic coating might have an added value in case of very specific aneurysms cases requiring the placement of a stent in the acute phase after rupture. Those specific cases are mainly dissecting or blister aneurysms for which endovascular or even surgical approach are difficult and carry a high risk of morbi-mortality. In case of endovascular treatment, recent meta-analyses have demonstrated the superiority of reconstructive techniques with flow diverter against deconstructive techniques despite the need for dual antiplatelet treatment with standard flow-diverter. However, those specific aneurysms represent a tiny minority of the endovascularly treated aneurysms. They account for only 0.3% to 1% of intracranial aneurysms and 0.9% to 6.5% of ruptured aneurysms[5–7]. Most of others ruptured aneurysms are suitable for surgical or endovascular treatments without any need for use of a stent in the acute phase. Also, in case of implantation of stent for unruptured aneurysms, the need for dual antiplatelet treatment does not carry a high ischemic risk and new antiplatelet treatments such as ticagrelor or prasugrel [9–14] recently helped to reduce the occurrence of this complication.
Beyond the potential indication of using PED shield with SAPT for ruptured aneurysms, we assume that PED-shield might be used with a SAPT in the setting of unruptured aneurysms. We recently followed this strategy in the setting of a 47-year-old woman allergic to aspirin with a medical history of severe angioedema and harboring an unruptured 11 mm left ophthalmic aneurysm. This patient had been premedicated with ticagrelor (Brilique 90 mg twice a day) and a PED-shield had been implanted without any trouble with perfect wall apposition improved with intra-stent balloon angioplasty. As routinely performed in our center, an MRI has been performed 24 hours after the treatment showing a normal patency of the flow-diverter without any ischemic complication on the DWI sequence. The patient has been discharged home on day 3 but suffered on day 6 of transient right arm palsy and right eye ptosis. An MRI has been performed in emergency depicting minimal ischemic lesions in the right MCA territory with an acute thrombosis of the stent. This patient improved with no deficit thanks to efficient supply from the Willis polygon. However, this observation illustrates the risk of using SAPT in the setting of intracranial stent implantation for the treatment of aneurysms even with the PED-shield device which has been presumed to carry low thrombogenicity.
In light of this observation, we would recommend further randomized clinical trial in order to assess the security of using SAPT treatment with the PED-Shield flow-diverter device.
1 Manning NW, Cheung A, Phillips TJ, et al. Pipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience. Journal of NeuroInterventional Surgery 2019;11:694–8. doi:10.1136/neurintsurg-2018-014363
2 Gonzalez AM, Narata AP, Yilmaz H, et al. Blood blister-like aneurysms: Single center experience and systematic literature review. European Journal of Radiology 2014;83:197–205. doi:10.1016/j.ejrad.2013.09.017
3 Kaschner MG, Kraus B, Petridis A, et al. Endovascular treatment of intracranial ‘blister’ and dissecting aneurysms. The Neuroradiology Journal 2019;32:353–65. doi:10.1177/1971400919861406
4 Rouchaud A, Brinjikji W, Cloft HJ, et al. Endovascular Treatment of Ruptured Blister-Like Aneurysms: A Systematic Review and Meta-Analysis with Focus on Deconstructive versus Reconstructive and Flow-Diverter Treatments. American Journal of Neuroradiology 2015;36:2331–9. doi:10.3174/ajnr.A4438
5 Nakagawa F, Kobayashi S, Takemae T, et al. Aneurysms protruding from the dorsal wall of the internal carotid artery. Journal of Neurosurgery 1986;65:303–8. doi:10.3171/jns.1986.65.3.0303
6 McLaughlin N, Laroche M, Bojanowski MW. Blister-like aneurysms of the internal carotid artery – management considerations. Neurochirurgie 2012;58:170–7. doi:10.1016/j.neuchi.2012.02.025
7 Abe M, Tabuchi K, Yokoyama H, et al. Blood blisterlike aneurysms of the internal carotid artery. Journal of Neurosurgery 1998;89:419–24. doi:10.3171/jns.1998.89.3.0419
8 Pikis S, Mantziaris G, Mamalis V, et al. Diffusion weighted image documented cerebral ischemia in the postprocedural period following pipeline embolization device with shield technology treatment of unruptured intracranial aneurysms: a prospective, single center study. Journal of NeuroInterventional Surgery 2019;:neurintsurg-2019-015363. doi:10.1136/neurintsurg-2019-015363
9 Atallah E, Saad H, Bekelis K, et al. The use of alternatives to clopidogrel in flow-diversion treatment with the Pipeline embolization device. Journal of Neurosurgery 2018;129:1130–5. doi:10.3171/2017.5.JNS162663
10 Moore JM, Adeeb N, Shallwani H, et al. A Multicenter Cohort Comparison Study of the Safety, Efficacy, and Cost of Ticagrelor Compared to Clopidogrel in Aneurysm Flow Diverter Procedures. Neurosurgery Published Online First: 5 May 2017. doi:10.1093/neuros/nyx079
11 Choi HH, Lee JJ, Cho YD, et al. Antiplatelet Premedication for Stent-Assisted Coil Embolization of Intracranial Aneurysms: Low-Dose Prasugrel vs Clopidogrel. Neurosurgery 2018;83:981–8. doi:10.1093/neuros/nyx591
12 Soize S, Foussier C, Manceau P-F, et al. Comparison of two preventive dual antiplatelet regimens for unruptured intracranial aneurysm embolization with flow diverter/disrupter: A matched-cohort study comparing clopidogrel with ticagrelor. Journal of Neuroradiology Published Online First: February 2019. doi:10.1016/j.neurad.2019.01.094
13 Barra ME, Berger K, Tesoro EP, et al. Periprocedural Neuroendovascular Antiplatelet Strategies for Thrombosis Prevention in Clopidogrel‐Hyporesponsive Patients. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2019;39:317–34. doi:10.1002/phar.2228
14 Dmytriw AA, Phan K, Salem MM, et al. The Pipeline Embolization Device: Changes in Practice and Reduction of Complications in the Treatment of Anterior Circulation Aneurysms in a Multicenter Cohort. Neurosurgery Published Online First: 12 March 2019. doi:10.1093/neuros/nyz059