6 OFF-LABEL USE



10.1055/b-0037-146680

6 OFF-LABEL USE

DENNIS J. RIVET II, JOHN REAVEY-CANTWELL, and CHRISTOPHER J. MORAN


Abstract


Flow diversion has been demonstrated to be an effective treatment for cerebral aneurysms as well as a variety of other cerebrovascular lesions. Aneurysms and other lesions, which were previously considered untreatable or treated only with significant rates of morbidity and mortality, are now treated on a routine basis and with greatly reduced neurological sequela. The Pipeline Embolization Device (PED) received Food and Drug Administration (FDA) approval in 2011 for relatively narrow range of indications. FDA approved uses or “on-label” indications are restricted to large cerebral aneurysms from the petrous segment through the superior hypophyseal segment in adults. However, the application of flow diversion techniques has great value in lesions which do not fit strictly within this classification and in fact, the majority of cases that are treated with flow diversion currently are classified as “off-label” for one or multiple reasons. Some of the most common clinical situations where flow diversion is used in this manner include recurrent aneurysms previously treated with alternative endovascular means; aneurysms located in the posterior circulation or segments distal to the original proximal-indicated segment; and pathologies such as dissecting, fusiform, and blister-type aneurysms. Given that some of these conditions and specific lesions are subjected to treatment with this technology, the complexity and breadth of treatment possibilities has expanded greatly. In this chapter, we highlight some of the most common off-label indications and provide illustrative cases as examples.




6.1 Introduction


The Pipeline Embolization Device (PED) was approved by the U.S. Food and Drug Administration (FDA) for use in the United States on April 6, 2011, with labeling indications that specified its use for the treatment of wide-necked, large (≥ 10 mm), or giant intracranial aneurysms in the internal carotid artery (ICA), from the petrous segment through the superior hypophyseal segment, in adults 22 years of age or greater. This chapter focuses on the clinical use of these stents for indications outside the original FDA approval or “off-label” use as initially designated for the PED. At the time of this writing, no other flow diversion technologies are approved for use in the United States. It is noteworthy that the majority of cases performed with the PED are off-label. For instance, 53% of the 893 aneurysm treatments included in the IntrePED registry were performed for an off-label indication. 1



6.2 Recurrent Aneurysms


The recurrence rate after initial aneurysm coiling is not insignificant with rates reported in the range of 15 to 20%. 2 , 3 , 4 Furthermore, the recurrence rate for recoiling of previously coiled aneurysms may be as high as 50%. 5 This makes these lesions a potentially attractive target for the off-label use of flow diversion devices. Daou et al utilized the PED in a series of recurrent aneurysms and of 30 previously coiled aneurysms with angiographic follow-up, and they found a rate of complete occlusion of 76.7% and near-complete (≥ 90%) occlusion of 86.7%. 6 Of the aneurysms treated with a PED, only 6.7% required retreatment.


Another frequent off-label application of flow diversion is, as a rescue strategy after treatment failure, using a stent-assisted coiling with a nitinol self-expanding stent ( Fig. 6.1). Recurrent aneurysms that have been previously treated with stent-assisted coiling can be difficult to access with a microcatheter due to endothelialization of the coils and stents. Flow diversion offers the advantage of avoiding the need to access the aneurysm through the hardware. However, this application is often challenging technically due to the difficulty in navigation of the microcatheter and flow diverter through the existing stent, obtaining adequate vessel wall apposition, or successful expansion of the flow diversion device if it becomes entangled in the preexisting stent(s) and coil construct. It is also worth noting that in the labeling indications ( Table 6.1), one of the four listed contraindications for use is the presence of a preexisting stent in the parent artery at the target aneurysm location.



























Table 6.1 Pipeline Embolization Device—FDA-approved indications and contraindications

Indications


Large or giant intracranial, wide-necked aneurysms


Anterior circulation, from petrous segment of ICA to superior hypophyseal artery


Adults aged 22 or older


Contraindications


Patients with active bacterial infection


Patients in whom dual antiplatelet therapy (aspirin and clopidogrel) is contraindicated


Patients who have not received dual antiplatelet agents prior to the procedure


Patients in whom a preexisting stent is in place in the parent artery at the target aneurysm location


Abbreviation: ICA, internal carotid artery.

Fig. 6.1 A 59-year-old woman with an incidentally discovered left internal carotid artery (ICA) aneurysm (a,b) measuring 18 × 19 × 16.5 mm with a wide neck. Patient underwent stent coiling with Guglielmi detachable coils and a 4.5 × 28 mm Enterprise VRD in 2009 (c,d). Patient was lost to followup until August 2015 when she returned with headaches. Angiography demonstrated a recurrent very wide-necked aneurysm in the left ICA posterior wall and posterior communicating artery segment with a 9 × 5 mm neck (e,f). The Enterprise stent extended from the cavernous ICA to the left M1 segment of the middle cerebral artery. Retreatment was performed with a Pipeline Flex 4.25 mm × 35 mm device supplemented by Axium coils. Initial posttreatment angiography is shown (g,h) with marked reduction in the opacification of the aneurysm and the neck. Six-month follow-up angiography showed complete obliteration of the aneurysm with the left A1 patent but with slow flow (i,j).

The use of a PED, however, has been reported in conjunction with the Neuroform stent, Enterprise stent, and the Leo + stent. Heiferman et al reported a series 7 of 25 aneurysms for which prior stent-assisted coiling had failed. Twenty-four of the 25 aneurysms were able to be treated and at 12-month follow-up, angiography showed Raymond class I obliteration in 38% (9 aneurysms) with all treated cases demonstrating decreased filling on follow-up imaging. Daou et al also reported a series of 21 patients with recurrent aneurysms initially treated with stent-assisted coiling. 8 The complete occlusion rate was 55.6%, which was a significantly lower obliteration rate than their own series of recurrent aneurysms that were originally treated with coiling alone. The retreatment (11.1%) and complication rates (14.3%) were also higher.


The majority of the cases treated in the aforementioned series involved aneurysms in the anterior circulation only. In addition, the reported complication rates (6–9%) are slightly higher in these series than the complication rates reported for recoiling procedures (1–3%). These results point to a potential cost for the higher occlusion rates when using flow diverters following stent-assisted coiling.



6.3 Ruptured Aneurysms


The treatment of ruptured aneurysms was traditionally believed to be contraindicated, given the gradual rate of aneurysm thrombosis resulting from flow diversion. It was believed that the risk of short-term morbidity and mortality, principally from re-rupture, would be too great to justify flow diversion as a protective strategy. In addition, the requirement for dual antiplatelet therapy complicated any additional surgical interventions for the patient, that is, the management of hydrocephalus with external ventricular drainage and/or shunt placement. However, as experience has accumulated, it has been increasingly recognized that flow diversion may be a reasonable option and can be accomplished with an acceptable outcome rate for a subset of ruptured aneurysms, with a particularly challenging morphology ( Fig. 6.2). 9 , 10 Lin et al 9 published a series of 26 patients treated with PED in the setting of subarachnoid hemorrhage (SAH). Eight of the 26 patients were treated in a delayed fashion and all but 4 patients had dissecting, fusiform, or blister aneurysms. In addition, 12 of the 26 patients were treated with adjunctive coiling along with flow diversion to accomplish a more immediate and complete aneurysm occlusion. Perioperative complications were seen in 19.2% of patients with three mortalities. Follow-up angiography was available for 23 of the patients with a 78.2% rate of aneurysm occlusion. A more complete review of flow diversion for ruptured aneurysms is covered elsewhere in this book.

Fig. 6.2 A 41-year-old woman with a mild headache 1 day prior to presentation that acutely became worst headache of life while using the bathroom. Head CT (a) showed a subarachnoid hemorrhage. Catheter angiography including 3D rotational angiography (bd) shows two small, irregular aneurysms at the right internal carotid artery (ICA) terminus and proximal middle cerebral artery. Endovascular treatment was elected and the aneurysm was treated with a single Pipeline 3 mm × 18 mm device deployed from the distal ICA into the M1 segment. Post–placement angiography showed coverage over both aneurysms and (e,f) increased cross-filling of the anterior cerebral artery (ACA) from the left (g,h) (continued). Post–placement angiography showed coverage over both aneurysms and (e,f) increased cross-filling of the anterior cerebral artery (ACA) from the left (g,h). Follow-up angiography at 1 year showed complete aneurysm occlusion, absent right A1 filling (i, j), and bilateral ACA filling from the left carotid injection (k).


6.4 Distal Anterior Circulation and Posterior Circulation Aneurysms


There are currently ongoing clinical trials which may expand the approved indications, if confirmed to have similar outcomes as the original studies that were the basis for FDA approval. The Pipeline Premier Trial expanded the indications to include aneurysms located throughout the intracranial course of the ICA up to the terminus, the vertebral artery up to and including the posterior inferior cerebellar artery (PICA), and aneurysms ≤ 12 mm in dimension. The follow-up collection period for the Premier Trial concluded in late 2016 with the hopes that these data may lead to broadening of indications to include the current clinical practice within the FDA-approved indications. It is also possible that if and when additional flow diversion devices are approved for use, the approved indications will be broader than the PED.


Currently, flow diversion with a PED can be an excellent, albeit, off-label solution for posterior circulation aneurysms ( Fig. 6.3, Fig. 6.4, Fig. 6.5). A proximal location of posterior circulation aneurysms reduces, but does not eliminate, the risk of occlusion of a perforating vessel. Additionally, an endovascular treatment may eliminate the risks for what can be a challenging surgical approach. However, perforators are oftentimes not visualized during the procedure and the rate of complications may rise with the use of multiple overlapping devices. 11 Patency of large branch vessels such as the PICA has been reported in multiple series and is presumed to occur due to downstream demand maintaining anterograde flow. In a small series of vertebral artery aneurysms located on the V4 segment, 8 of 11 patients maintained PICA patency despite coverage with the PED at follow-up without evidence of clinical sequela. 12

Fig. 6.3 A 69-year-old man with a 1-week history of severe headaches. CT head (a) showed no SAH but a hyperdense lesion anterior to the brainstem. MRI (b,c) and MRA (d,e) were performed and showed a left vertebral artery aneurysm at the pontomedullary junction, projecting posteriorly and superiorly. MRI (b,c) and MRA (d,e) were performed and showed a left vertebral artery aneurysm at the pontomedullary junction, projecting posteriorly and superiorly. Cerebral angiography (f,g) showed the lesion was located at the terminal left vertebral artery and measured 7.5 mm. This was treated with a single Pipeline device placed proximal to the vertebrobasilar junction (h). One-year follow-up angiography (i,j) showed complete aneurysm occlusion.
Fig. 6.4 A 62-year-old woman with multiple medical problems referred for treatment of an incidentally detected left vertebral artery fusiform aneurysm discovered on a contrast-enhanced CT scan of the head (a). Angiography demonstrated a fusiform aneurysmal dilation of the left vertebral artery at the site of the left posterior inferior cerebellar artery (PICA) origin as well as a 14-mm saccular portion to the aneurysm adjacent to this (b,c). This was treated with a 4.5 mm × 20 mm Pipeline device (d). These intraoperative images show stasis of contrast within the saccular component of the aneurysm and no change in filling of the PICA. Follow-up angiography at 6 months showed a small residual component to the saccular aneurysm and improvement in the fusiform portion (e). At 2-year follow-up, only a small portion of the saccular portion remained (f). This was completely occluded at 3-year follow-up and the PICA remained patent (g).
Fig. 6.5 A 51-year-old woman who presented to an outside hospital in a delayed manner after the worst headache of her life, which initially began as severe posterior neck pain. The patient used medications for the symptoms for 8 days and then presented to medical attention. CT scan and lumbar puncture were negative for evidence of hemorrhage. CT angiography (a, arrow) demonstrated a left vertebral artery aneurysm and the patient was transferred for treatment. Angiography confirmed a 11 × 9 × 7 mm dissecting left vertebral artery aneurysm spanning the origin of the posterior inferior cerebellar artery (PICA; b, arrows). After treatment with dual antiplatelet therapy, the patient was treated with flow diversion using a single 4 mm × 20 mm Pipeline device. Follow-up angiography 2.9 years after treatment demonstrated no in-stent stenosis, occlusion of the aneurysm, normal caliber to the vertebral artery, and antegrade filling of the PICA (c).

Flow diversion has also been used effectively in more distal posterior circulation segments, where other treatment options would have distinct disadvantages ( Fig. 6.6). However, the initial experience with posterior circulation flow diversion, particularly with fusiform aneurysms, was filled with significant morbidity and mortality from both perforator infarcts and delayed ruptures. 13

Fig. 6.6 A 15-year-old female with a history of chronic headaches presented with a 2-week history of severe headaches. Head CT showed a diffuse SAH, intraventricular hemorrhage, and mild hydrocephalus. The date that the hemorrhage occurred was unknown based on history. A ventriculostomy was placed and a cerebral angiography was performed. This showed an atypical basilar artery aneurysm, consistent with a dissecting-type aneurysm, just below the superior cerebellar artery (SCA) origins with a duplicated left SCA (ac). She was treated with CSF drainage for 11 days and the ventriculostomy was weaned and then removed. She was then loaded with dual antiplatelet therapy and treated with a 3.0 × 18 mm Pipeline which was advanced into the right posterior cerebral artery (PCA) and deployed from the proximal R PCA to the distal basilar artery. (d) Intraoperative single series fluoroscopic views after placement of the device with stasis of contrast within the aneurysm. (e) Dual volume 3D angiography, depicting the relationship of the stent to the aneurysm and terminal basilar artery. Angiography at 1 year (f) showed no evidence of residual aneurysm and anterograde filling of the bilateral PCA and superior cerebellar artery arteries.

Albuquerque et al, 14 however, published a series of 17 cases with more than 90% complete or near-complete occlusion. Only one patient experienced a significant complication related to a ventriculostomy hemorrhage. Munich et al 11 reported a series of 12 fusiform vertebrobasilar aneurysms treated with PED and reported one death and two significant new neurological complications, both of which improved significantly at follow-up. At follow-up, 90% of the cases were angiographically occluded. In a subsequent reanalysis of the treatment indication after their initial cautionary report, the University of Buffalo group published 15 a series of 12 patients with fusiform vertebrobasilar aneurysms treated with flow diversion with 50% of the cases treated with adjunctive coiling. At last radiological follow-up (14-month average), all 12 patients had patent devices and complete aneurysm occlusion. Two patients did require a second treatment with a PED to achieve complete occlusion. Only one patient suffered a perforator infarct. In these and other reports, 16 multiple factors are cited which may have improved the outcomes and make posterior circulation aneurysm viable treatment targets. These strategies included adjunctive coiling to limit delayed rupture, limiting the number of devices utilized as longer Pipeline device lengths became available, and meticulous attention to dual antiplatelet efficacy and adherence. Although this represents small retrospective case series, the results lend support to the use of flow diversion in cases where alternatives, such as stent-assisted coiling, clip reconstruction, or deconstructive procedures with or without bypass, are not feasible or carry similar substantial risks.


The distal anterior circulation is another area of off-label use that has expanded as experience has been gained ( Fig. 6.7, Fig. 6.8, Fig. 6.9). Initial published reports 17 , 18 did not seem to validate concerns regarding coverage of A1 and M1 segments and perforators. Additionally, the technical feasibility of navigating devices into smaller distal vessels has been well documented. Lin et al 18 reported successful treatment of 27 distal anterior circulation aneurysms with PEDs in a series that included fusiform (15), dissecting (5), and saccular (8) aneurysms. They reported a perioperative complication rate of 10.7% and complete aneurysm occlusion in almost 80% at an average follow-up of 10.7 months. It is noteworthy that 10 of the 27 cases had failed previous treatment with either clipping or coiling.

Fig. 6.7 A 66-year-old left-handed man presents with altered mental status. Head CT showed a spherical hyperdensity in the region of the anterior communicating artery with adjacent vasogenic edema (a). Contrast-enhanced CT showed a partially thrombosed anterior communicating artery aneurysm (b). Cerebral angiography confirmed a large partially thrombosed anterior communicating artery aneurysm supplied by the left A1 only (c). This was treated with placement of a 2.5 × 14 mm PED in the left anterior cerebral artery (ACA) from the A2 segment back into the distal A1, with an Echelon microcatheter jailed in the aneurysm (d) and then coiling of the aneurysm with 23 Axium coils. There was complete occlusion of the aneurysm. The procedure was complicated by the development of intra-arterial thrombus formation, within the Pipeline device (e, arrow), noted at the completion of the coiling. This responded to intra-arterial abciximab infusion, followed by 12 hours of postoperative intravenous abciximab infusion without neurological complication. At 23-month follow-up, there was patency of the left ACA, no recurrence of the aneurysm (f), and no filling of the aneurysm from the right internal carotid artery (not shown).
Fig. 6.8 A 49-year-old man who suffered a right frontal traumatic intraparenchymal hematoma after a motorcycle collision 3 months prior to presentation. He then had a fall and underwent CT of the head which revealed a right frontal lesion concerning for an anterior cerebral artery (ACA) aneurysm (a). MRI was performed (b) which showed right frontal lobe posttraumatic encephalopathy with an adjacent rounded focus of signal abnormality, most likely a pseudo-aneurysm, and an additional area of chronic intraparenchymal hemorrhage surrounding the pseudoaneurysm. Angiography showed a 9-mm pseudoaneurysm of the left A2 segment which better opacifies from the right carotid injection (c), and a relatively avascular area in the right ACA territory from the hematoma and encephalomalacia. A microcatheter run (d) in the left A2 demonstrated a right callosomarginal artery (double line arrow) originating from the left A2 as well as the left pericallosal (arrow) artery originating from the left A2 (arrowhead), which gives rise to the aneurysm. At treatment, an initial 2.5 × 10 mm PED device was deployed distal to the aneurysm neck; therefore, a second 2.75 × 10 mm device was placed at the proximal end and overlapping the first. There was stasis of contrast in the aneurysm after PED placement (e,f) and stable occlusion of the pseudoaneurysm at the 1-year follow-up (g).
Fig. 6.9 A 53-year-old woman originally presented with a Hunt-Hess Grade 2 SAH. She was found to have a left middle cerebral artery aneurysm with adjacent fusiform dilatation in the M1 segment (a,b). She underwent craniotomy and clipping. Intraoperative angiography demonstrated a small dog-ear remnant (arrow on lateral projection, c). The patient lived out of state and was lost to follow-up. Two years later, she re-presented with a recurrent Hunt-Hess Grade 2 SAH (d). Angiography showed a recurrence of the aneurysm and progression of the fusiform changes in the left M1 segment (eg). She was loaded with aspirin and clopidogrel and treated with flow diversion the day following presentation. An Echelon microcatheter was jailed in the aneurysm by deploying a Pipeline 4 × 20 mm device from the M1 segment back into the internal carotid artery. (h) The device during deployment with the microcatheter in the aneurysm. A microwire was left within the microcatheter for stability. (i) The device immediately after deployment. There was no residual filling of the aneurysm after completion of coiling and placement of the Pipeline (j,k). There was no residual filling of the aneurysm after completion of coiling and placement of the Pipeline (j,k). Angiography performed 6 months later showed interval decrease in the fusiform dilatation of the M1 segment and no recurrence of the aneurysm (l).

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May 23, 2020 | Posted by in NEUROSURGERY | Comments Off on 6 OFF-LABEL USE
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