Pipeline Flex embolisation device with Shield Technology for the treatment of complex intracranial aneurysms

Full details of all clinical outcomes considered by the committee are available in the assessment report overview.

The key clinical outcomes for Pipeline presented in the decision problem are:

• successful device deployment

• successful occlusion of the aneurysm, with or without preservation of flow through the parent vessel

• size of the aneurysm and its contained thrombus mass

• resolution of symptoms (including headache, diplopia, nystagmus or other neurological dysfunction), relief of pain and quality of life outcomes

• resource use outcomes (for example, re-admission rates, repeat interventions and duration of hospital stay)

• stroke related to device insertion (any cause, but particularly due to vessel occlusion or bleeding)

• delayed parent vessel occlusion

• subarachnoid haemorrhage and/or other major bleeding events needing admission to hospital

• neurovascular death

• device-related adverse events.

The sponsor identified 13 studies relevant to the scope, but because it judged the quality of many of these to be poor and because of duplication in patient reporting, the sponsor's submission presented detailed findings on a total of 139 patients from 2 studies, with a maximum follow-up of 2 years. The studies were Pipeline for Intracranial Treatment of Aneurysms (PITA) and Pipeline for Uncoilable or Failed aneurysms (PUFS).

Nelson et al. (2011) reported outcomes up to 2 years for the PITA study: a prospective, multicentre single-arm feasibility study of 31 patients with 31 intracranial aneurysms that were small (under 10 mm [20 patients]), large (10 mm to 25 mm [9 patients]) or giant (over 25 mm [2 patients]). An aneurysm neck width of 4 mm or more was recorded in 22 patients (71%). In 12 patients (39%), other interventions for the target aneurysm had failed.

A report to the FDA by the sponsor (FDA 2011) described the clinical evidence at 1 year from the PUFS study: an ongoing prospective, multicentre, single-arm study of 108 patients with 110 intracranial aneurysms that were small (under 10 mm [1 patient]), large (10 mm to 25 mm [85 patients]) or giant (over 25 mm [22 patients]). The mean aneurysm neck width was 8.8 mm. In 8 patients (7%), other interventions for the target aneurysm had failed.

In its literature search, the external assessment centre found 3 case reports and 1 conference abstract of 96 patients in addition to the 13 studies identified by the sponsor. It excluded 1 of the studies identified by the sponsor (Matouk et al. 2010) because it was outside the scope. The external assessment centre therefore included a total of 16 studies with 380 patients in its assessment report.

Across 13 studies with a total of 237 patients (239 complex intracranial aneurysms), successful device placement was reported in 50% to 100% of patients. In 8 of the 13 studies, successful device placement was reported in all patients (25 in total; Fiorella et al. 2008, 2009a, 2009b, 2010; Hartmann et al. 2010; Kilsch et al. 2011; Phillips et al. 2010; Sararols et al. 2011).

Nelson et al. (2011) reported clinical procedure success (defined as successful placement of the device without death or ipsilateral stroke) in 94% (29 of 31) of patients: the 2 failures were because of peri-procedural stroke. For patients in the PUFS study, the primary effectiveness end point was complete occlusion of the aneurysm and absence of parent vessel stenosis greater than 50% at 180 days. The probability of exceeding the pre-determined 'success threshold' of 50% was statistically significant (p<0.0001; FDA, 2011).

Major ipsilateral stroke or neurological death, as judged by the Clinical Events Committee, was reported in 6% (6 of 107) of patients at 180 days in the PUFS study (FDA 2011). Ipsilateral stroke was reported in 7% (2 of 31) of patients within 30 days in the PITA study (Nelson et al. 2011). Five other studies including a total of 58 patients (68 complex intracranial aneurysms) reported a stroke rate of 0% at follow-up ranging from 10 weeks to more than 52 weeks (Fiorella et al. 2009a, 2009b; Lylyk et al. 2009a; Klisch et al. 2011; Sararols et al. 2011).

In the PUFS study, 3 of the 6 patients who had a major ipsilateral stroke died (timing of events not reported). Nelson et al. (2011) reported no deaths in the PITA study.

Nelson et al. (2011) reported complete occlusion of the target aneurysm in 93% (28/30) of patients at 180 days (95% confidence interval [CI] 77.9 to 99.2); it was not possible to assess occlusion in 1 patient who had Pipeline surgically removed and the parent vessel ligated. All patients who had complete occlusion at 180 days also had complete occlusion at 2 years as assessed by either catheter angiography or MRI.

Complete occlusion without major stenosis was reported in 74% (78 of 106) of aneurysms at 180 days and 71% (75 of 106) of aneurysms at 1‑year angiography (FDA 2011). Eight studies with a total of 131 patients all reported occlusion rates of 100% in patients assessed at follow-up ranging from 3 to 30 months (Fiorella et al. 2008, 2009a, 2009b, 2010; Klisch et al. 2011; Phillips et al. 2010; Sararols et al. 2011; Szikora et al. 2010b). Occlusion rates of 93%, 89% and 69% were reported by Lylyk et al. (2009a), Szikora et al. (2010a) and O'Kelly et al. (2011) respectively (absolute figures not reported).

Nelson et al. (2011) reported that 10% (3 of 31) of patients, 1 of whom had previously had a stroke, showed improvement in intracranial aneurysm-related symptoms at 30 days. There was no deterioration in neurological status at 30 days in the 28 patients free of stroke. The FDA report (2011) described Rankin scoring (a general measure of neurological function) for 104 patients. The scores improved from baseline in 20% (21 of 104) of patients, remained unchanged in 67% (70 of 104) and deteriorated in 10% (10 of 104) at 180 days follow-up. There was an improvement in visual field sensitivity (not otherwise described) from baseline in 21% (19 of 89) of patients, no change in 73% (65 of 89) of patients and deterioration in eye function in 6% (5 of 89) of patients at follow-up of 180 days (FDA 2011). Three case reports described complete resolution of symptoms at follow-up ranging from 10 to 26 weeks (Fiorella et al. 2009a, 2009b; Sararols et al. 2011). Szikora et al. (2010b) reported resolution of symptoms in 61% of patients at a mean follow-up of 26 weeks.

Studies of 96, 18, 8 and 5 patients reported subarachnoid haemorrhage after surgery in 1%, 5%, 13% and 20% of patients respectively (absolute figures and follow-up not reported; Hampton et al. 2011; Hartmann et al. 2010; O'Kelly et al. 2011, Szikora et al. 2010b).