Impact of SAMMPRIS: Polling Results From the ICAD Symposium
Impact of SAMMPRIS: Polling Results From the ICAD Symposium
Limited data exist on the effect of the SAMMPRIS trial results on the current clinical treatment of ICAD. Our polling results from the 2012 ISC suggest that SAMMPRIS has had a significant impact on the current clinical management of ICAD and may influence future trials.
The SAMMPRIS trial results demonstrated the superiority of aggressive medical therapy over PTAS, with a 30-day rate of stroke or death of 5.8% in the medical management arm compared with 14.7% in the PTAS group. Our poll showed that 84% of respondents felt that patients with ICAD should be treated with a regimen of aspirin and clopidogrel for 3 months followed by aspirin only and rosuvastatin (with the goal of LDL <70 mg/dl) (figure 1C). These results suggest a shift in the medical management of ICAD patients with the recent findings of SAMMPRIS, as the recommendation from the Warfarin-Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial was aspirin alone. Although opinions varied widely on how to treat patients who fail aggressive medical therapy, only 18% indicated that they would continue the patient on aggressive medical therapy while 53% would perform angioplasty and stenting or angioplasty alone. Given the results of SAMMPRIS, our poll demonstrates that physicians are still willing to perform interventions on patients with ICAD who fail aggressive medical therapy.
Registries Data from previous registries supported the efficacy of PTAS in the SAMMPRIS patient population; however, the reported 30-day rate of stroke or death was much lower in these studies than in the PTAS arm of SAMMPRIS (5.2–9.6% vs 14.7%). Of the respondents, 51% agreed that registries play a vital role in clinical decision-making post-SAMMPRIS and 40% indicated that an independently funded/adjudicated single-arm prospective registry should be the next step after SAMMPRIS. Although data from one or two moderately-sized randomized controlled trials (RCTs) of ICAD (SAMMPRIS: 451 patients; Vitesse Stent Study for Ischemic therapy (VISSIT) trial: 112 patients (data release pending)) may address the above limitations and guide future RCTs, low-cost large-volume registries may be required to understand the natural history of ICAD and evaluate endovascular techniques before embarking on future RCTs. The results of SAMMPRIS suggest that retrospective preliminary self-reported data without independent blinded adjudication may not be a firm basis for RCTs. Future registry/phase II studies need to be prospective and independently adjudicated, with patient inclusion and exclusion criteria closely mirroring the criteria of the anticipated phase III RCT.
Lead-in phase When polled regarding the design of the next clinical trial, attendees strongly supported a lead-in phase for future ICAD device trials which may be attributable to the success of the Carotid Revascularisation Endarterectomy versus Stenting Trial (CREST). The CREST trial yielded extremely low surgical and endovascular complication rates, probably the result of a rigorous credentialing process that included a lead-in phase. In a device RCT, roll-in or lead-in phases may be of added value as they allow the operator additional experience and evaluation of the device before the start of the trial. However, depending on the complexity or novelty of a device, lead-in cases may not be necessary. In the recent Solitaire With the Intention for Thrombectomy (SWIFT) trial, experience with the Solitaire flow restoration device was required on only two roll-in subjects and a strong benefit was shown relative to the Merci retrieval system. While SAMMPRIS did not involve a lead-in phase, credentialing was based on documented outcomes and experience with the Wingspan stent system and similar devices. An analysis of indicators of physician experience and outcomes in the SAMMPRIS trial found no indication that inexperience led to the higher than expected complication rates in the trial. Careful consideration must be given to the pros and cons of roll-in and lead-in phases, and whether inclusion of these phases may be of benefit in the next ICAD RCT.
Patient population Patient selection will be a critical factor in the design of future RCTs of endovascular therapy in ICAD. The SAMMPRIS trial targeted a subset of the ICAD population (≥70% stenosis) thought to carry the highest risk of recurrent stroke. Data from the WASID trial demonstrated a higher cumulative rate of stroke in patients with ≥70% stenosis (18% at 1 year) compared with those with <70% stenosis (6% at 1 year). When polled regarding the next ICAD trial patient population, 48% of attendees strongly preferred patients with recurrent stroke or TIA despite aggressive medical therapy (ie, SAMMPRIS-style) (figure 3B). These results demonstrate a shift from the SAMMPRIS population which included patients who experienced a TIA or non-disabling stroke but were not required to have failed antithrombotic therapy. The SAMMPRIS patient population differed from the original trial where Wingspan gained humanitarian device exemption (HDE) approval as the 45 patients enrolled had all failed antithrombotic medication. A recent subgroup analysis of SAMMPRIS revealed that 63% of patients were enrolled after having a qualifying event on antithrombotic medication; however, only 22% of these patients were on dual antiplatelet therapies (aspirin and clopidogrel). No prospective studies are currently available to define antithrombotic failure, and future definitions should focus on identifying high-risk patients with medically refractory ICAD who may benefit from endovascular therapy.
Recently, the US Food and Drug Administration (FDA) released a safety communication (August 2012) regarding the limited selection of patients with ICAD for treatment using the Wingspan stent system. The narrowed indication for use of Wingspan was based on current analysis of the original HDE clinical study, studies performed after the HDE approval and data from the SAMMPRIS trial. The Wingspan is now approved for patients meeting all of the following criteria: (1) age 22–80 years; (2) two or more strokes despite aggressive medical management; (3) most recent stroke occurring more than 7 days prior to planned intervention; (4) 70–99% stenosis due to atherosclerosis of the related intracranial artery; and (5) good recovery from previous stroke and modified Rankin score of ≤3 prior to intervention. Given the FDA's recent recommendation which was based on all available safety information from Wingspan, the patient population of the next ICAD trial may potentially mirror the FDA's inclusion criteria.
For potential candidate populations, 66% of attendees felt that patients with hemodynamic border zone strokes should be included in future prospective studies. In several ICAD studies, collateral circulation was shown as a strong determinant of stroke risk in intracranial atherosclerosis. In a post hoc analysis of the WASID trial population, the extent of collaterals was a predictor for recurrent stroke in the territory of the symptomatic artery for all degrees of stenosis. A recent subanalysis of the SAMMPRIS trial demonstrated that patients with poor perfusion and poor collaterals had a higher occurrence of primary events downstream from the stenosis (23% in the PTAS group, 20% in the aggressive medical therapy group). Patients with poor collateral flow and persistent symptoms may represent a subgroup of the SAMMPRIS population with a higher risk of stroke despite aggressive medical therapy. Prospective studies are needed to examine whether this subset of high-risk patients may benefit from endovascular therapies such as primary angioplasty.
Intervention Although the SAMMPRIS trial has provided valuable data on intracranial stenting in ICAD, it only evaluated a single device system and technique (the Wingspan stent system with PTAS) and did not evaluate other devices such as balloon-mounted stents or balloon angioplasty alone. The results of the SAMMPRIS trial underscore the need for developing and testing new and effective treatments for patients with symptomatic ICAD in clinical trials. When polled with regard to the next ICAD clinical trial post-SAMMPRIS, 29% of participants were supportive of a clinical trial comparing primary balloon angioplasty with aggressive medical therapy (figure 3A). Several studies have suggested that primary balloon angioplasty is a safe and acceptable alternative to stent placement and may reduce periprocedural complication rates, especially in technically challenging lesions. A recent multicenter study of 74 patients with ICAD treated with primary balloon angioplasty reported a 30-day stroke rate of 5% (4/74; 95% CI 1.5% to 13%), a technical success rate (defined as residual stenosis ≤50%) of 92% (95% CI 83% to 97%) and a 3-month stroke/death rate of 8.5% (6/71; 95% CI 3.1% to 17.5%). In a multicenter review in which outcomes were compared for 190 patients with ICAD treated with 95 primary angioplasty and 98 intracranial stent procedures (193 procedures) from three tertiary centers, no difference in the 2-year stroke and/or death survival rate was found between the angioplasty-treated and the stent-treated groups (92±4% and 89±5%, respectively). These initial findings suggest the feasibility of primary angioplasty as a treatment for ICAD; however, prospective studies are needed to determine the efficacy of angioplasty in the context of aggressive medical therapy prior to initiating a RCT.
Discussion
Limited data exist on the effect of the SAMMPRIS trial results on the current clinical treatment of ICAD. Our polling results from the 2012 ISC suggest that SAMMPRIS has had a significant impact on the current clinical management of ICAD and may influence future trials.
Clinical Management of ICAD
The SAMMPRIS trial results demonstrated the superiority of aggressive medical therapy over PTAS, with a 30-day rate of stroke or death of 5.8% in the medical management arm compared with 14.7% in the PTAS group. Our poll showed that 84% of respondents felt that patients with ICAD should be treated with a regimen of aspirin and clopidogrel for 3 months followed by aspirin only and rosuvastatin (with the goal of LDL <70 mg/dl) (figure 1C). These results suggest a shift in the medical management of ICAD patients with the recent findings of SAMMPRIS, as the recommendation from the Warfarin-Aspirin for Symptomatic Intracranial Arterial Stenosis (WASID) trial was aspirin alone. Although opinions varied widely on how to treat patients who fail aggressive medical therapy, only 18% indicated that they would continue the patient on aggressive medical therapy while 53% would perform angioplasty and stenting or angioplasty alone. Given the results of SAMMPRIS, our poll demonstrates that physicians are still willing to perform interventions on patients with ICAD who fail aggressive medical therapy.
Clinical Trials Post-SAMMPRIS
Registries Data from previous registries supported the efficacy of PTAS in the SAMMPRIS patient population; however, the reported 30-day rate of stroke or death was much lower in these studies than in the PTAS arm of SAMMPRIS (5.2–9.6% vs 14.7%). Of the respondents, 51% agreed that registries play a vital role in clinical decision-making post-SAMMPRIS and 40% indicated that an independently funded/adjudicated single-arm prospective registry should be the next step after SAMMPRIS. Although data from one or two moderately-sized randomized controlled trials (RCTs) of ICAD (SAMMPRIS: 451 patients; Vitesse Stent Study for Ischemic therapy (VISSIT) trial: 112 patients (data release pending)) may address the above limitations and guide future RCTs, low-cost large-volume registries may be required to understand the natural history of ICAD and evaluate endovascular techniques before embarking on future RCTs. The results of SAMMPRIS suggest that retrospective preliminary self-reported data without independent blinded adjudication may not be a firm basis for RCTs. Future registry/phase II studies need to be prospective and independently adjudicated, with patient inclusion and exclusion criteria closely mirroring the criteria of the anticipated phase III RCT.
Lead-in phase When polled regarding the design of the next clinical trial, attendees strongly supported a lead-in phase for future ICAD device trials which may be attributable to the success of the Carotid Revascularisation Endarterectomy versus Stenting Trial (CREST). The CREST trial yielded extremely low surgical and endovascular complication rates, probably the result of a rigorous credentialing process that included a lead-in phase. In a device RCT, roll-in or lead-in phases may be of added value as they allow the operator additional experience and evaluation of the device before the start of the trial. However, depending on the complexity or novelty of a device, lead-in cases may not be necessary. In the recent Solitaire With the Intention for Thrombectomy (SWIFT) trial, experience with the Solitaire flow restoration device was required on only two roll-in subjects and a strong benefit was shown relative to the Merci retrieval system. While SAMMPRIS did not involve a lead-in phase, credentialing was based on documented outcomes and experience with the Wingspan stent system and similar devices. An analysis of indicators of physician experience and outcomes in the SAMMPRIS trial found no indication that inexperience led to the higher than expected complication rates in the trial. Careful consideration must be given to the pros and cons of roll-in and lead-in phases, and whether inclusion of these phases may be of benefit in the next ICAD RCT.
Patient population Patient selection will be a critical factor in the design of future RCTs of endovascular therapy in ICAD. The SAMMPRIS trial targeted a subset of the ICAD population (≥70% stenosis) thought to carry the highest risk of recurrent stroke. Data from the WASID trial demonstrated a higher cumulative rate of stroke in patients with ≥70% stenosis (18% at 1 year) compared with those with <70% stenosis (6% at 1 year). When polled regarding the next ICAD trial patient population, 48% of attendees strongly preferred patients with recurrent stroke or TIA despite aggressive medical therapy (ie, SAMMPRIS-style) (figure 3B). These results demonstrate a shift from the SAMMPRIS population which included patients who experienced a TIA or non-disabling stroke but were not required to have failed antithrombotic therapy. The SAMMPRIS patient population differed from the original trial where Wingspan gained humanitarian device exemption (HDE) approval as the 45 patients enrolled had all failed antithrombotic medication. A recent subgroup analysis of SAMMPRIS revealed that 63% of patients were enrolled after having a qualifying event on antithrombotic medication; however, only 22% of these patients were on dual antiplatelet therapies (aspirin and clopidogrel). No prospective studies are currently available to define antithrombotic failure, and future definitions should focus on identifying high-risk patients with medically refractory ICAD who may benefit from endovascular therapy.
Recently, the US Food and Drug Administration (FDA) released a safety communication (August 2012) regarding the limited selection of patients with ICAD for treatment using the Wingspan stent system. The narrowed indication for use of Wingspan was based on current analysis of the original HDE clinical study, studies performed after the HDE approval and data from the SAMMPRIS trial. The Wingspan is now approved for patients meeting all of the following criteria: (1) age 22–80 years; (2) two or more strokes despite aggressive medical management; (3) most recent stroke occurring more than 7 days prior to planned intervention; (4) 70–99% stenosis due to atherosclerosis of the related intracranial artery; and (5) good recovery from previous stroke and modified Rankin score of ≤3 prior to intervention. Given the FDA's recent recommendation which was based on all available safety information from Wingspan, the patient population of the next ICAD trial may potentially mirror the FDA's inclusion criteria.
For potential candidate populations, 66% of attendees felt that patients with hemodynamic border zone strokes should be included in future prospective studies. In several ICAD studies, collateral circulation was shown as a strong determinant of stroke risk in intracranial atherosclerosis. In a post hoc analysis of the WASID trial population, the extent of collaterals was a predictor for recurrent stroke in the territory of the symptomatic artery for all degrees of stenosis. A recent subanalysis of the SAMMPRIS trial demonstrated that patients with poor perfusion and poor collaterals had a higher occurrence of primary events downstream from the stenosis (23% in the PTAS group, 20% in the aggressive medical therapy group). Patients with poor collateral flow and persistent symptoms may represent a subgroup of the SAMMPRIS population with a higher risk of stroke despite aggressive medical therapy. Prospective studies are needed to examine whether this subset of high-risk patients may benefit from endovascular therapies such as primary angioplasty.
Intervention Although the SAMMPRIS trial has provided valuable data on intracranial stenting in ICAD, it only evaluated a single device system and technique (the Wingspan stent system with PTAS) and did not evaluate other devices such as balloon-mounted stents or balloon angioplasty alone. The results of the SAMMPRIS trial underscore the need for developing and testing new and effective treatments for patients with symptomatic ICAD in clinical trials. When polled with regard to the next ICAD clinical trial post-SAMMPRIS, 29% of participants were supportive of a clinical trial comparing primary balloon angioplasty with aggressive medical therapy (figure 3A). Several studies have suggested that primary balloon angioplasty is a safe and acceptable alternative to stent placement and may reduce periprocedural complication rates, especially in technically challenging lesions. A recent multicenter study of 74 patients with ICAD treated with primary balloon angioplasty reported a 30-day stroke rate of 5% (4/74; 95% CI 1.5% to 13%), a technical success rate (defined as residual stenosis ≤50%) of 92% (95% CI 83% to 97%) and a 3-month stroke/death rate of 8.5% (6/71; 95% CI 3.1% to 17.5%). In a multicenter review in which outcomes were compared for 190 patients with ICAD treated with 95 primary angioplasty and 98 intracranial stent procedures (193 procedures) from three tertiary centers, no difference in the 2-year stroke and/or death survival rate was found between the angioplasty-treated and the stent-treated groups (92±4% and 89±5%, respectively). These initial findings suggest the feasibility of primary angioplasty as a treatment for ICAD; however, prospective studies are needed to determine the efficacy of angioplasty in the context of aggressive medical therapy prior to initiating a RCT.
