SAMMPRIS

Intracranial atherosclerotic arterial stenosis is one of the major causes of ischemic stroke. Due to high rates of recurrent strokes on medical management, there has been a growing cautious hope that intracranial angioplasty and stenting could further reduce stroke risk in select high-risk individuals. The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), was a randomized controlled trial comparing the safety and efficacy of the Wingspan Stent System and Gateway PTA Balloon Catheter (Boston Scientific Corporation, Natick, MA) plus aggressive medical therapy in the treatment of intracranial atherosclerotic stenosis vs aggressive medical management alone. On April 5, 2011, the Data and Safety Monitoring Board of this study recommended that enrollment be stopped due to safety concerns after an interim analysis showed a significantly higher rate of periprocedural stroke in the stenting arm.1 A total of 451 patients were enrolled with 227 patients randomized to the medical-management group and 224 to percutaneous transluminal angioplasty and stenting (PTAS). Symptomatic patients with a transient ischemic attack or a stroke within 30 days prior to presentation due to a severe stenosis (70%-99%) of a major intracranial artery were included. Aggressive medical management was defined as aspirin at a dose of 325 mg per day, clopidogrel at the dose of 75 mg per day for 90 days, and close management of risk factors (hypertension, high cholesterol levels, diabetes, smoking, excess weight, and lack of exercise). Patients in the stenting arm also received the same aggressive medical therapy. The primary endpoint of stroke or death within 30 days of enrollment was significantly higher in the PTAS arm (14.7% vs 5.8%, P = 0.002). Ten of the 33 (30.3%) strokes observed in the stenting group were hemorrhagic whereas no patient in the medical treatment arm suffered a hemorrhagic stroke (P = 0.04). All strokes occurred within 6 days of the stenting procedure with 25 occurring on post-revascularization day 1. Operator and center experience were found to be irrelevant with the rates of periprocedural events remaining constant throughout the study period. The primary endpoint of stroke in the corresponding arterial territory beyond 30 days after enrollment excluding the periprocedural rates was similar between both groups with 13 nonfatal ischemic strokes recorded in each group. The difference between the 2 treatment arms was still significant in favor of medical management though when computing all primary endpoints for the entire follow-up period (P = 0.009) (Figure). The rate of death or any stroke, which was the secondary endpoint of the study, was similar between both groups (16.3% in the medical arm and 23.2% in the PTAS group, P = 0.06) but the rate of any stroke and any major hemorrhage was significantly higher in the stenting group.Figure: Kaplan-Meier curves of the cumulative pro?bability of the primary end point. PTAS, percutaneous transluminal angioplasty and stenting. Permission to reprint granted by the Massachusetts Medical Society (Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003.)Like with any good clinical trial, SAMMPRIS adds to our knowledge but it also raises many questions. While the conclusion that medical management alone is superior to stenting plus medical management seems warranted based on the data one has to consider several issues to reach more nuanced conclusions. When analyzing a clinical trial one has to consider the possibility of hidden confounding factors which may have influenced the results. Along these lines several questions can be reasonably raised. The SAMMPRIS trial defined intracranial stenosis based on symptomatology and degree of stenosis. Length of stenosis and location were not used as stratifying features. In our opinion, a short segment symmetric petrous carotid artery stenosis has a very different procedural risk profile compared to a long segment asymmetric basilar artery stenosis. Additionally, other variables including nature and age of plaque and angulation and tortuosity of the affected artery will likely influence stenting outcomes. In a study by Mori et al2 simple lesions (short and non-occlusive) had a 92% rate of procedural success with angioplasty and an 8% rate of stroke whereas the more complex lesions had a 33% rate of procedure success and an unacceptable 87% rate of stroke. Such variables were not taken into account when patients were randomized in SAMMPRIS and could have potentially constituted hidden confounding factors. Further, disease behavior varies greatly amongst different populations. While SAMMPRIS was conducted exclusively in the United States, intracranial atherosclerosis is most prevalent in Asian populations. This fact strains the external validity of the trial.3,4 Patients who underwent stenting in SAMMPRIS had higher rates of stroke compared to previous registries using the same Wingspan stent.5-7 Alarmingly, the rate of hemorrhagic strokes was also significantly higher than in previous reports. This high rate of hemorrhagic stroke is unexplained and raises questions regarding operator experience and perioperative management of blood pressure. While the SAMMPRIS investigators did their best to account for operator experience, it remains legitimate to question the potential role of operator relative inexperience in this study. Although results did not improve with time and experience according to the SAMMPRIS data, intracranial stenting technology has not been around for a long enough time to analyze and understand operator proficiency and improvement trends. This is an important issue particularly since intracranial vessels have unique characteristics that make them more delicate to navigate. The sharp acute angles, their intrinsic histological features, and the lack of reinforcing connective tissue (intracranial vessels float in cerebrospinal fluid) render them more prone to injury and dissection thus making stenting technically challenging. In addition, one could argue that the better results obtained in the registries was perhaps in part due to the fact that the number of patients needed for the trial was much higher and therefore less experienced centers were needed to meet enrollment requirements. Although the credentialing process required the interventionist to have performed at least 20 intracranial stenting or angioplasty procedures, only 3 had to have been done using the Wingspan stent. In addition, stenting for aneurysms was accepted as well as angioplasty without stenting. Angioplasty alone is arguably not equivalent to stenting in terms of difficulty and adverse events.8 Also, stenting for an?eurysms is quite different technically from stenting for stenosis and proficiency in one technique does not necessarily transfer completely to the other. Given the relative novelty of dedicated devices for intracranial atherosclerosis, the question is whether better stent technology dedicated to overcoming the challenges of intracranial navigation would improve procedural safety and efficacy. The ongoing VISSIT study may help us gain better insight into these issues.9 Also, further refining the strategy of stenting technique—perhaps staged angioplasty followed by stenting?10—might increase procedural safety by making the plaque more fibrotic and stable with minimal balloon manipulation. Finally, it is evident that further refinements in plaque and brain imaging are needed. Are certain plaques more prone to procedural complications based on their biology and or morphology? Advanced magnetic resonance imaging with perfusion and molecular imaging may increase our sophistication in this area.11-13 Regarding the implications of SAMPRIS, the question of what to do about patients who fail medical therapy should be contemplated. What about the patients who continue to be symptomatic and experience strokes despite optimal medical therapy and control of risk factors? In the absence of proven better alternatives, should stenting or angioplasty alone be considered and discussed as valid treatment options? Importantly it should be noted that patients enrolled in this trial as in all trials had to be considered “equally” manageable by both treatment options thus limiting our ability to extrapolate the results to patients who are severely symptomatic despite optimal medical management. Therefore, the external validity of the trial is limited to the confines of the rigid inclusion and exclusion criteria set by the investigators and should not be generalized ?to all patients. Ultimately, the SAMPRIS investigators should be congratulated and commended for their contribution to our sparse knowledge base on issues related to intracranial atherosclerosis. This trial has clearly demonstrated the value of aggressive medical management for symptomatic high-grade intracranial atherosclerosis. Clearly, further refinements in endovascular devices are needed to reduce treatment risk. In addition, further refinements in patient selection, preoperative physiological imaging of the plaque and brain tissue, greater operator experience, and perioperative management may create opportunities to enhance the natural history of symptomatic intracranial atherosclerosis with endovascular intervention.