Published online before print June 21, 2012, doi: 10.3174/ajnr.A3201
AJNR 2012 33: E107

G.P. Colby^a, L.-M. Lin^a and A.L. Coon^a
aDepartment of Neurosurgery
Johns Hopkins University School of Medicine
The Johns Hopkins Hospital
Baltimore, Maryland

We read with interest the recent case series by Cruz et al,¹ reporting their experience with the Pipeline Embolization Device (PED; Chestnut Medical Technologies, Menlo Park, California) in 66 patients with 47 anterior circulation aneurysms. The emphasis of this article was on the high rate of delayed (1–6 days postprocedure) ipsilateral intraparenchymal hemorrhage (IPH) in 4 of 47 patients (8.5%). The authors proposed that these adverse events are unlikely secondary to aneurysm characteristics or intraprocedural events but are rather due to hemodynamic changes and altered arterial compliance of the parent vessel caused by the PED.

What is most alarming, the rate of IPH in this series by Cruz et al¹ is significantly higher than that in all other large series of PED embolizations published to date. A recent review by Fargen et al² of complications associated with the PED from 7 large series reported a total IPH count of 4 in 374 patients treated (1.1%). This rate is in line with the annual risk of dual antiplatelet therapy alone,³ when used for secondary stroke prevention,⁴ and lower than the IPH rate of 2.2% reported after stent-assisted coiling.⁵ The article by Fargen et al did not include our recently published series of 34 patients, in which there were no instances of IPH.⁶ To date, we have treated 56 patients with 68 aneurysms (60 anterior circulation, 8 posterior circulation) with no ICH events (0%). If we add our results to the data compiled for the article by Fargen et al, there are a total of 4 ICH events in 430 treated patients, or 0.9%. This rate is 10-fold lower than that reported by Cruz et al.

As described above, various mechanisms have been proposed to explain IPH after PED embolization. Given the variable rates of IPH in the literature, it is unlikely that these events are intrinsic to the PED itself. Alterations in parent vessel compliance and hemodynamics also do not fully explain these events because IPH rates should be more uniform across multiple series. If changes in vessel compliance from the PED increased the risk of IPH, implantation of longer length devices or telescoped multidevice constructs should result in more cases of IPH. This has not been observed in the published literature or in our personal series.⁶

We have stressed that the PED is not simply a device but rather a set of complex, customizable techniques.^6,7 Vessel manipulation during PED treatment can be substantial in certain cases, particularly when establishing robust proximal access and during PED deployment in tortuous vessels. Great care must be taken at multiple steps to avoid iatrogenic embolic events, endothelial injury, and significant vasospasm—all of which can cause stroke and have the potential for hemorrhagic conversion. Avoidance and reduction of adverse outcomes requires careful attention to patient selection, user technique, and postprocedure management. These variables should be at the forefront of any discussion of adverse outcomes, particularly when there is a discrepancy between the outcomes achieved at different centers. Flow diversion for treatment of aneurysms is still in its infancy, and discussions such as this about outcomes and techniques are important to further improve and optimize treatment paradigms for our patients.

References

1. Cruz JP, Chow M, O’Kelly C, et al. Delayed ipsilateral parenchymal hemorrhage following flow diversion for the treatment of anterior circulation aneurysms. AJNR Am J Neuroradiol 2012;33:603–08 » Abstract/FREE Full Text
2. Fargen KM, Velat GJ, Lawson MF, et al. Review of reported complications associated with the Pipeline embolization device. World Neurosurg 2012;77:403–04 » CrossRef » Medline
3. Serebruany VL, Malinin AI, Ferguson JJ, et al. Bleeding risks of combination vs. single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients. Fundam Clin Pharmacol 2008;22:315–21 » CrossRef » Medline
4. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–37 » CrossRef » Medline
5. Shapiro M, Becske T, Sahlein D, et al. Stent-supported aneurysm coiling: a literature survey of treatment and follow-up. AJNR Am J Neuroradiol 2012;33:159–63 » Abstract/FREE Full Text
6. Colby GP, Lin LM, Gomez JF, et al. Immediate procedural outcomes in 35 consecutive Pipeline embolization cases: a single-center, single-user experience. J Neurointerv Surg 2012 Mar 29. [Epub ahead of print]
7. Colby GP, Gomez JF, Lin LM, et al. In situ removal of the Pipeline embolization device: the ‘corking’ and ‘pseudo-corking’ techniques. J Neurointerv Surg 2012 Feb 23. [Epub ahead of print]

Reply

Published online before print June 21, 2012, doi: 10.3174/ajnr.A3220
AJNR 2012 33: E108

J.P. Cruz^a
aDepartment of Medical Imaging
University of Toronto
Toronto, Ontario, Canada

C. O’Kelly^b
bDivision of Neurosurgery, Department of Surgery
University of Edmonton
Edmonton, Alberta, Canada

J. Spears^c and T.R. Marotta^c
cDepartment of Medical Imaging
Saint Michael’s Hospital
University of Toronto
Toronto, Ontario, Canada

We thank Dr Colby and colleagues for their summary of the existing literature as well as their own recent publication of a retrospective, self-adjudicated series of 41 aneurysms in 34 patients treated with the Pipeline Embolization Device (PED; Chestnut Medical Technologies, Menlo Park, California), in which they observed no parenchymal hemorrhages.¹ They did observe 1 fatal subarachnoid hemorrhage, which they attributed to spontaneous rupture of a previously unruptured 3-mm paraclinoid aneurysm after treatment, and 1 ischemic stroke, for an overall permanent neurologic complication rate of 6%. With respect to selection, half (51%) of the aneurysms in this series were small (<10 mm), and the average size was only 11.4 mm. This average is likely skewed by the subset of larger extradural aneurysms, which constituted one-third of their series. Thus, this series represents a substantial extrapolation from the existing trial data supporting the application of the PED and its labeled indications for use.While Dr Colby and associates have observed no delayed ipsilateral parenchymal hemorrhages in their series, they are at an early stage in their Pipeline experience. On the basis of 34 cases with no hemorrhages, the 95% confidence intervals for a zero percent incidence of delayed hemorrhage are as high as 8.8%. If 1 hemorrhage occurs during their next case, the rate at their institution will be 3% (ie, triple their expected rate based on composite self-adjudicated “literature”).

Given the limitations involved with self-reported retrospective series, we think that the best data to analyze are from independently adjudicated clinical trials like Pipeline for Uncoilable and Failed Aneurysms (PUFS) and Complete Occlusion of Coilable Intracranial Aneurysms. In these studies of anterior circulation aneurysms, the overall rate of parenchymal hemorrhage was 5.2% (6 hemorrhages in 116 patients)—not very different from our observed incidence (FDA Executive Summary of PUFS).² It is difficult to imagine how patient selection was an issue with these subjects because their inclusion in the trial was based on predefined inclusion and exclusion criteria. In addition, it is difficult to argue that technical expertise or bad judgment played a role within these trials, which included only the most experienced operators in the world. The observation that these hemorrhages were all ipsilateral to the treated aneurysm is an important and compelling finding that is difficult to ignore. This pattern strongly suggests that these events are somehow related to the procedure and/or device rather than just attributable to dual antiplatelet therapy. The timeframe during which they occur—days to weeks after treatment—and the observation that the affected patients have typically been neurologically normal for days preceding the ictus essentially excludes a simple mechanical explanation such as a distal wire perforation or a problem related to “vessel manipulation.”

Delayed ipsilateral parenchymal hemorrhage is a relatively novel complication observed in a new class of interventional devices. We must continue to evaluate these cases for commonalities and search for plausible explanations. Only by identifying the root causes of this complication will we be able to enact procedures to avoid it and optimize the application of this technology. Claiming that it will never happen to me because I am careful does little to advance our understanding of this phenomenon and is a disservice to future patients.

References

1. Colby GP, Lin LM, Gomez JF, et al. Immediate procedural outcomes in 35 consecutive Pipeline embolization cases: a single-center, single-user experience. J Neurointerv Surg 2012 Mar 29. [Epub ahead of print]
2. Food and Drug Administration. Summary of safety and effectiveness data. Pipeline Embolization Device. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMater
   ials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPan
   el/UCM247165.pdf