The results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial were published recently in the New England Journal of Medicine.1 The trial was a randomized controlled trial which was sponsored by the National Institutes of Health (clinicaltrials.gov number, NCT0057693). Entrance into the trial required the presence of a symptomatic 70–99% stenosis of a large vessel intracranial artery (internal carotid, M1 segment of middle cerebral artery, vertebral or basilar). Patients had to be randomized within 30 days of their qualifying event. Patients were randomized to receive either maximum medical therapy alone or maximum medical therapy in combination with angioplasty and stenting of the target lesion using the Gateway/Wingspan system (Boston Scientific/Stryker, Fremont, CA, USA). The maximum medical therapy regimen was defined as: aspirin 325 mg/ day; clopidogrel 75 mg/day for 90 days after enrolment; management of primary risk factors (elevated systolic blood pressure and elevated low density lipoprotein cholesterol levels) and management of secondary risk factors (diabetes, elevated non-high density lipoprotein cholesterol levels, smoking, excess weight and insufficient exercise). The study provided enrolled patients aspirin, clopidogrel, one drug from each major class of antihypertensive agents and rosuvastatin. In the stenting arm, the Gateway/Wingspan system was provided to the patient. Lifestyle modification was facilitated by a study provided ‘lifestyle coach’.

The study results demonstrated a higher than expected 30 day stroke rate in the stent plus medical therapy arm (14.7%) and a lower than expected 30 day stroke rate in the medical therapy alone arm (5.8%). The estimated 1 year stroke rate for the medically treated arm is 12.2%. The difference in the 30 day stroke rate between the two arms was statistically significant. Reporting of the results from ongoing follow-up of accrued patients and subset analysis is anticipated.

The organizers and investigators of the SAMMPRIS trial should be applauded for their efforts in this endeavor. The results of the trial should act as a guideline for future clinical practice patterns as well as future trial designs. Unfortunately, the interpretation of these results by the lay press as well as selective individual physicians has led some to an unfortunate negative focus on US regulatory bodies and the initial humanitarian device exemption (HDE) approval of the Gateway/Wingspan system by the FDA. The authors feel that the initial HDE approval was completely appropriate at the time as it was based on the natural history from the Warfarin–Aspirin Symptomatic Intracranial Disease Study (WASID) trial of an estimated 24.9%/year stroke risk for patients with a symptomatic >70% stenosis who were treated with WASID defined medical therapy as well as a reasonable risk profile of angioplasty/stenting, as estimated from registry data.2–6

While the results of SAMMPRIS may be difficult for members of the neurointerventional community to accept, it is imperative that we strive to use the best existing evidence to guide our treatment of patients. However, the estimated 1 year stroke rate of 12.2% in the medically treated arm of SAMMPRIS is not insignificant. For this reason, SAMMPRIS should not be the end of new innovations in both medical and endovascular interventions for symptomatic intracranial atherosclerotic disease (ICAD). While future trials may be more difficult to complete and involve larger numbers of patients, it is important that we continue to seek to improve outcomes for patients with this potentially devastating condition. It is entirely possible that an intervention (eg, percutaneous transluminal angioplasty (PTA) alone, single step PTA plus stent implantation (PTAS) with a balloon expandable device or stenting with a rapid exchange delivery system) could result in lower periprocedure (with 30 days) and postprocedure (30 days to 1 year) event rates.

Also, while providing important information, the initial results of the SAMMPRIS trial leave some questions at this point regarding ICAD and its management unanswered. While some of these questions may be answered with subsequent subset analysis and long term patient follow-up data, others may remain unanswered without further study due to the limitations of study design as well as the limited patient population size. In general, some of the major remaining questions revolve around the topics of anatomy/physiology, timing of the intervention, technology and patient/physician/socioeconomic factors.

With regards to anatomy/physiology, it is doubtful that the natural history of stroke and the procedural risk of revascularization is the same for different anatomical locations (petrous and cavernous internal carotid versus M1 and mid-basilar arteries). Also, it is probable that for patients who have a clear hemodynamic basis for their symptoms the risk:benefit ratio of revacularization would be altered compared with medical therapy. Although this may represent a smaller subset of total ICAD patients, their tenuous clinical condition and overall poor prognosis in this patient population suggests a role for revascularization as opposed to medical therapy alone. Perhaps physiological imaging may play a role in identifying this subset of patients although this would have to be studied further.

Additionally, the question of timing of revascularization in relation to acute stroke symptoms needs to be answered. By design, SAMMPRIS patients who were randomized to the angioplasty/stent arm were treated relatively soon after their inclusion event. It is conceivable that early stenting may increase the periprocedural risk profile due to plaque instability and untoward hemodynamic effects on already ischemic tissue. Additionally, aggressive intraprocedural heparinization in addition to dual antiplatelet therapy in this early setting may increase the risks of hemorrhagic complications related to the procedure.

With regards to technology, the stent arm of SAMMPRIS required use of the Gateway/Wingspan system (Boston Scientific/Stryker). This was reasonable as this system had been approved by the FDA for this indication and there was growing operator experience with the system. In fact, SAMMPRIS was conducted at the highest volume centers for PTAS in the country by a group of rigorously credentialed and closely monitored operators. However, we know from experience that the evolution of other neurointerventional devices has led to improved treatment effectiveness and improved patient outcomes. Improvement of coil designs for endovascular aneurysm therapy is one example of this. Similarly, it is probable that improvements in future endovascular revascularization technologies will improve the risk profile of the procedure. One would hope that the results of this one trial will not be a barrier for industry to strive toward these improvements. Finally, as alluded to above, it is unclear from the SAMMPRIS results whether a subset of patients might be better served with angioplasty alone as this was not examined in the study.

With regards to patient/physician/socioeconomic factors, is unclear how the risk:benefit ratio of revascularization might vary according to age, sex and race of the patient. Also, perhaps most importantly, it is unclear how well the risk reduction of maximum medical therapy, as outlined in the SAMMPRIS trial, will translate to the ‘real world’ setting. While it is probable that the protective effect of medical therapy in relation to the 30 day event rate in SAMMPRIS was primarily due to the dual antiplatelet regimen and possibly cholesterol management rather that other aspects of lifestyle modification due to the short time frame, it is uncertain whether physicians outside of the trial (including non-neuroscience specialists) will be as fastidious as the trial investigators were with regards to the risk reduction regimen they prescribe. Also, it is uncertain whether patient compliance will be a factor in the ‘real world’ when medications are not provided for free and there is no ‘lifestyle coach’ to help alter behavior patterns.

In summary, the completion of the SAMMPRIS trial is truly a landmark for the fields of neurointervention and vascular neurology. We are hopeful that the trial acts as motivation for further studies to answer the many remaining questions regarding management of individual patients with the serious and potentially life threatening condition of intracranial atherosclerotic disease.