SAMMPRIS Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis Khalil Zahra, M.D
Major points Patients with recent TIA or stroke and intra-cranial artery stenosis of 70 to 99% are at very high risk of recurrent stroke in the territory of the stenotic artery. Enrollment in the SAMMPRIS Trial was halted after 451 patients underwent randomization. The WASID trial previously placed the 30-day rate of stroke or death at 10.7% and a 1-year rate at 25%. SAMMPRIS was directed at investigating the safety and efficacy of treatment with the Wingspan stent in addition to aggressive medical management alone
The trial was unexpectedty stopped prior to the planned duration because of increased stroke risk among those who received percutaneous transluminal angioplasty and stenting. This was due to both a higher than expected rate of peri-procedural stroke in patients who underwent PCTA (14.7%) compared to Phase I and II trials with the Wingspan stent AND a lower than expected rate of primary end points in the medical managed group ( 5.8 %) compared to data from WASID. The probability of experiencing the primary end point (any stroke or death within 30 days after enrollment or after any revascularization procedure of a qualifying lesion or a stroke in the territory of the symptomatic artery beyond 30 days) at 1 year was 20% in the endovascular therapy group and 12.2% in the medical management group 3
DESIGN Multicenter, randomized controlled trial N=451 PTAS + Aggressive Medical Therapy (n=224) 198 had stent placements in this group, procedure was not performed in 4 patients, the procedure was aborted before the lesion was accessed in 7, and angioplasty alone was performed in 5 Aggressive Medical Therapy Only (n=227) 9 (4.0%) underwent PTAS after a repeat CVA after the initial event Setting:50 centers in the United States Enrollment: Oct 2008-April 2011 Mean follow-up: 11.9 months at time of publication Analysis: Intention-to-treat Primary outcome: Stroke or death within 30 days of initiation of treatment or stroke in the territory of the qualifying artery beyond 30 days. 4
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Guidlines For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70% 99%) of a major intracranial artery, the addition of clopidogrel 75 mg/d to aspirin for 90 days might be reasonable (Class IIb; Level of Evidence B). For patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the data are insufficient to make a recommendation regarding the usefulness of clopidogrel alone, the combination of aspirin and dipyridamole, or cilostazol alone (Class IIb; Level of Evidence C). 7
For patients with a stroke or TIA attributable to moderate stenosis (50% 69%) of a major intracranial artery, angioplasty or stenting is NOT recommended given the low rate of stroke on medical management and the inherent peri-procedural risk of endovascular treatment (Class III; Level of Evidence B). For patients with stroke or TIA attributable to severe stenosis (70% 99%) of a major intracranial artery, stenting with the Wingspan stent system is NOT recommended as an initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA (Class III; Level of Evidence B). 8
WASID Trial In the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, the risk of major vascular events was high when patients received either warfarin (8.4 events per 100 patient-years) or aspirin (18.1 per 100 patientyears). In this trial the inclusion and exclusion criteria were almost similar to the SAMMPRIS. 9
SAMMPRIS Angioplasty was performed for patients with symptomatic ICAD (stenosis of 70% 99% of the diameter of the affected artery) with a balloon undersized to approximately 50% 70% of the non diseased vessel diameter 10
TRIAL IMPLICATIONS The trial publication implicates 2 reasons for the disparity between the medical therapy group and the endovascular therapy group. First, the medical management arm had markedly lower rates of stroke than those seen in the preceding Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. Second, the 30-day stroke or death rate in the endovascular group was much higher than previously reported with the use of the trial device. 11
Trial Flaws The endovascular arm of the SAMMPRIS trial was conducted with a single device system: The Gateway angioplasty balloon and Wingspan stent. Was the device ready for the trial ( 2005 initial FDA approval based on limited study and the SAMMPRIS study protocol was first received by the National Institutes of Health in December 2007 and the study began in October 2008. Initial trial was based on stenosis of 50% stenosis. 12
NIHSS data Registry The only study that reported the stroke or death rate within 30 days or stroke in the territory of stenting beyond 30 days was the National Institutes of Health registry study. The authors concluded that the data from the registry when compared with high-risk patients from the WASID trial do not rule out either that stenting could be associated with a substantial relative risk reduction (eg, 50%) or has no advantage compared with medical therapy. 13
Role of Volume and Experience The high rate of stroke in the endovascular arm of the study was not attributed by the SAMMPRIS investigators to inexperience. The SAMMPRIS investigators reached a quite different conclusion regarding inexperience with the earlier publication of the National Institutes of Health registry data. In this publication, significant differences were found between the high and low enrolling sites for stroke or death within 30 days and for stroke in the territory of the treated artery after 30 days. The authors pointed out that although the rate of any stroke or death within 30 days or stroke in the territory beyond 30 days was 14% at 6 months for the entire group, it was 9% at high enrolling sites versus 23% at low enrolling sites, suggesting with greater experience the primary outcome measure would decrease in stented patient 14
Inherent high risk to the procedures with the device used in the trial, which does not decline with user experience. 2 step procedure: The need of 6Fr system. Long exchange wire system ( NOT rapid exchange)which may lead to higher complication. 15
Can these procedures be performed with a low rate of periprocedural complication? Some factors that could influence the rate of periprocedural complication may not have been optimized in SAMMPRIS. Two prominent factors are lesion morphology and choice of device. Lesion length and Morphology: Mori A, B, C. 16
Device systems Trackability and rigidity To date, no single device or technique has emerged that conclusively provides low complication rates, reduces stroke risk long-term, and is clearly superior to other available devices. The angioplasty balloon and the balloon-expandable stent have some common inherent procedural advantages over the Wingspan system. They can be introduced through a smaller 5-Fr catheter system. Some authors have been proponents of angioplasty balloons alone without stent placement or using stent rescue where angioplasty has caused a suboptimal result. 17
The Wingspan stent system has demonstrated relatively high rates of in-stent stenosis, particularly in the anterior circulation. A small number of publications with limited patient numbers and limited follow-up have suggested that drug-eluting stents may reduce restenosis rates. A recent report showed a 5-fold decrease in restenosis rates in patients treated with a drug-eluting angioplasty balloon as compared with conventional angioplasty balloons (9% versus 50%). 18
Where do we go from here? The results of the SAMMPRIS trial should not stop further investigation of endovascular therapy for severe symptomatic intracranial stenosis. The trial gave us useful information regarding the outcome for these symptomatic patients with medical management showing that even with aggressive highly monitored medical management, there was a 12.2% combined 30day stroke and death rate or ipsilateral stroke rate beyond 30 days in the first year of treatment 19
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Angioplasty without stenting represents an alternative. Submaximal angioplasty limits the risks of thromboembolism, vessel perforation, and reperfusion hemorrhage that were frequently reported with stenting in the SAMMPRIS trial 21
Angioplasty was performed with a balloon undersized to approximately 50% 70% of the non- diseased vessel diameter in patients with symptomatic ICAD who had angiographically significant stenosis of 70%. Among the 65 patients with symptomatic ICAD who were screened, 24 had significant angiographic stenosis that met the inclusion criteria of this study. 22
Most patients (75%) had anterior circulation stenosis. The mean preprocedure stenosis was 80.16%. Submaximal angioplasty was performed in patients who met the inclusion criteria, with a mean postangioplasty stenosis rate of 54.62% (median 55.5%, range 31% 78%). Rates of ischemic stroke in the territory of the treated artery were 0% within 30 days and 5.55% (in the only patient who presented with recurrent stroke) at 1 year. The mortality and hemor- rhage rates in this series were 0%. 23
Studies to date comparing surgical treatment with bypass (the Carotid Occlusion Surgery Study [COSS] or endovascular treatment with stenting (the aforementioned SAMMPRIS trial) have been terminated because of the failure of intervention to demonstrate superior stroke prevention when compared to medical treatment alone. 24
Additional studies with longer follow-up and a larger cohort are required to assess the true safety and efficacy of this technique for reduction of recurrent stroke from ICAD and to determine the patient population that will derive the greatest benefit. 25
EFFICACY The efficacy of the submaximal angioplasty technique in the setting of ICAD remains unclear. It is possible that patients benefit from this technique due to a marginal but adequate restoration of blood flow. Because flow is proportional to the fourth power of the radius of the affected artery (Poiseuille s equation), a small augmentation in diameter is adequate to restore functional distal territory flow in most cases. 34
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