Harry J. Cloft

Stenting versus aggressive medical therapy for intracranial arterial stenosis

BACKGROUND Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. METHODS We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. RESULTS Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. CONCLUSIONS In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

Predictors of Ischemic Stroke in the Territory of a Symptomatic Intracranial Arterial Stenosis

Background— Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy. Methods and Results— WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis ≥70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (≤17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk. Conclusions— Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis ≥70%, after recent symptoms, and in women.

Risk of Cerebral Angiography in Patients With Subarachnoid Hemorrhage, Cerebral Aneurysm, and Arteriovenous Malformation A Meta-Analysis

BACKGROUND AND PURPOSE A well-defined complication rate of cerebral angiography in patients with subarachnoid hemorrhage (SAH), cerebral aneurysm, and arteriovenous malformation (AVM) would be useful to physicians making decisions regarding the imaging of these patients. We sought to define a statistically significant complication rate through meta-analysis of prospective studies in the literature. METHODS Meta-analysis of 3 published prospective studies of complications in cerebral angiography was performed to specifically define the risk of cerebral angiography in patients presenting with SAH, cerebral aneurysm, and AVM. The complication rates for cerebral angiography in patients with SAH and AVM/aneurysm without SAH were compared with the complication rates in patients who underwent cerebral angiography for transient ischemic attack (TIA)/ischemic stroke with use of the Fisher exact test. RESULTS The combined risk of permanent and transient neurological complication was significantly lower in patients with SAH compared with patients with TIA/stroke (1.8% versus 3.7%; P=0.03). The combined risk of permanent and transient neurological complication was significantly lower in patients with aneurysm/AVM without SAH compared with patients with TIA/stroke (0.3% versus 3.7%; P=0.001). When the patients with SAH and cerebral aneurysm/AVM were combined, the overall risk of permanent and transient neurological complication was significantly lower than for the TIA/stroke patients (0.8% versus 3.0%; P=0.001), as was the risk of permanent neurological complication (0.07% versus 0.7%; P=0.004). CONCLUSIONS The risk of permanent neurological complication associated with cerebral angiography in patients with SAH, cerebral aneurysm, and AVM is quite low (0.07%). This risk is lower than previously recognized.

Posterior Reversible Encephalopathy Syndrome: Associated Clinical and Radiologic Findings

OBJECTIVE To identify and define clinical associations and radiologic findings of posterior reversible encephalopathy syndrome (PRES). PATIENTS AND METHODS Patients prospectively diagnosed as having PRES from October 1, 2005, through April 30, 2009, were pooled with retrospectively identified patients admitted from August 1, 1999, through September 30, 2005. We performed a detailed review of clinical information, including demographics, presenting symptoms, medical history, and risk factors. All patients underwent computed tomography of the brain or magnetic resonance imaging. Findings on magnetic resonance imaging were analyzed independently by 2 neuroradiologists. RESULTS We identified 120 cases of PRES in 113 patients (mean age, 48 years). Mean peak systolic blood pressure was 199 mm Hg (minimum-maximum, 160-268 mm Hg), and mean peak diastolic blood pressure was 109 mm Hg (minimum-maximum, 60-144 mm Hg). Etiologies of PRES included hypertension (n=69 [61%]), cytotoxic medications (n=21 [19%]), sepsis (n=8 [7%]), preeclampsia or eclampsia (n=7 [6%]), and multiple organ dysfunction (n=1 [1%]). Autoimmune disease was present in 51 patients (45%). Clinical presentations included seizures (n=84 [74%]), encephalopathy (n=32 [28%]), headache (n=29 [26%]), and visual disturbances (n=23 [20%]). In the 115 cases (109 patients) for which magnetic resonance imaging findings were available, the parieto-occipital regions were the most commonly involved (n=108 [94%]), followed by the frontal lobe (n=88 [77%]), temporal lobe (n=74 [64%]), and cerebellum (n=61 [53%]). Cerebellar involvement was significantly more frequent in patients with a history of autoimmunity (P=.008), and patients with sepsis were more likely to have cortical involvement (P<.001). CONCLUSION A substantial proportion of patients with PRES have underlying autoimmune conditions that may support endothelial dysfunction as a pathophysiologic mechanism. On brain imaging, the location and severity of vasogenic edema were mostly similar for the different clinical subgroups.

Endovascular Treatment of Intracranial Aneurysms With Flow Diverters: A Meta-Analysis

Background and Purpose— Flow diverters are important tools in the treatment of intracranial aneurysms. However, their impact on aneurysmal occlusion rates, morbidity, mortality, and complication rates is not fully examined. Methods— We conducted a systematic review of the literature searching multiple databases for reports on the treatment of intracranial aneurysms with flow-diverter devices. Random effects meta-analysis was used to pool outcomes of aneurysmal occlusion rates at 6 months, and procedure-related morbidity, mortality, and complications across studies. Results— A total of 29 studies were included in this analysis, including 1451 patients with 1654 aneurysms. Aneurysmal complete occlusion rate was 76% (95% confidence interval [CI], 70%–81%). Procedure-related morbidity and mortality were 5% (95% CI, 4%–7%) and 4% (95% CI, 3%–6%), respectively. The rate of postoperative subarachnoid hemorrhage was 3% (95% CI, 2%–4%). Intraparenchymal hemorrhage rate was 3% (95% CI, 2%–4%). Perforator infarction rate was 3% (95% CI, 1%–5%), with significantly lower odds of perforator infarction among patients with anterior circulation aneurysms compared with those with posterior circulation aneurysms (odds ratio, 0.01; 95% CI, 0.00–0.08; P<0.0001). Ischemic stroke rate was 6% (95% CI, 4%–9%), with significantly lower odds of perforator infarction among patients with anterior circulation aneurysms compared with those with posterior circulation aneurysms (odds ratio, 0.15; 95% CI, 0.08–0.27; P<0.0001). Conclusions— This meta-analysis suggests that treatment of intracranial aneurysms with flow-diverter devices is feasible and effective with high complete occlusion rates. However, the risk of procedure-related morbidity and mortality is not negligible. Patients with posterior circulation aneurysms are at higher risk of ischemic stroke, particularly perforator infarction. These findings should be considered when considering the best therapeutic option for intracranial aneurysms.

A New Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms

Background and Purpose— We report a preclinical study of a new endoluminal device for aneurysm occlusion to test the hypothesis that the device, even without use of intrasaccular coil placement, could occlude saccular aneurysms without causing substantial parent artery compromise or compromise of adjacent, small branch arteries. Methods— The Pipeline Neuroendovascular Device (Pipeline NED; Chestnut Medical Technologies, Inc) is a braided, tubular, bimetallic endoluminal implant aimed at occlusion of saccular aneurysms through flow disruption along the aneurysm neck. The device was implanted across the necks of 17 elastase-induced aneurysms in the New Zealand white rabbit model and followed for 1 month (n=6), 3 months (n=5), and 6 months (n=6). In each subject, a second device was implanted in the abdominal aorta to cover the origins of lumbar arteries. Aneurysm occlusion rates by angiography (grade 1, complete occlusion; grade 2, near-complete occlusion; and grade 3, incomplete occlusion) were documented. Percent area stenosis of the parent arteries was calculated. Presence of distal emboli in the downstream vessels in the parent artery and branch artery stenosis or occlusion was noted. Results— Grades 1, 2, and 3 occlusion rates were noted in 9 (53%), 6 (35%), and 2 (12%) of 17 aneurysms, respectively, indicating an 88% rate of complete or near complete occlusion. No cases of branch artery occlusion or distal emboli in the downstream vessels of the parent artery, specifically the subclavian artery, were seen. Parent artery compromise from neointimal hyperplasia was minimal in most cases. Conclusions— The Pipeline NED is a trackable, bio- and hemocompatible device able to occlude saccular aneurysms with preservation of the parent artery and small, adjacent branch vessels.

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomised trial

BACKGROUND Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). INTERPRETATION The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. FUNDING National Institute of Neurological Disorders and Stroke (NINDS) and others.

The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial

Background: Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography. Study Design: SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography. Results: SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained. Conclusions: Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.

Collaterals dramatically alter stroke risk in intracranial atherosclerosis

Stroke risk due to intracranial atherosclerosis increases with degree of arterial stenosis. We evaluated the previously unexplored role of collaterals in modifying stroke risk in intracranial atherosclerosis and impact on subsequent stroke characteristics.

A Second-Generation, Endoluminal, Flow-Disrupting Device for Treatment of Saccular Aneurysms

BACKGROUND AND PURPOSE: We report a preclinical study of a second-generation endoluminal device (Pipeline Embolization Device [PED-2] for aneurysmal occlusion and compare the PED-2 with its first-generation predecessor (PED-1). MATERIALS AND METHODS: Our Institutional Animal Care and Use Committee approved all studies. The PED-2 is a braided endoluminal, flow-diverting device and was implanted across the necks of 18 elastase-induced aneurysms in New Zealand white rabbits and followed for 1 month (n = 6), 3 months (n = 6), and 6 months (n = 6). A second PED-2 was implanted in the abdominal aorta to cover the origins of the lumbar arteries. Angiographic occlusion rates were documented as complete, near-complete, and incomplete. Parent artery percent diameter stenosis was calculated. Results were compared with a previous publication focused on the PED-1, with use of the same model. We compared ordinal outcomes using Fisher Exact or χ2 tests. We compared continuous data using analysis of variance. RESULTS: Occlusion rates (complete and incomplete) for the PED-2 were noted in 17 cases (94%) and 1 (6%), respectively, compared with 9 cases of complete (53%) and 8 (47%) of incomplete occlusion with the PED-1 (P = .0072). No incidents of branch artery occlusion or distal emboli in vessels downstream of the parent artery were observed with the PED-2. Parent artery neointimal hyperplasia was minimal in most cases and was significantly less than in the PED-1. CONCLUSIONS: The PED-2 is a biocompatible and hemocompatible device that occludes saccular aneurysms while preserving the parent artery and small-branch vessels in our animal model.