Intracranial Stenting for Stroke Prevention–The Lessons from SAMMPRIS
Hesham Masoud, MD and Thanh Nguyen, MD, FRCPC
Corresponding to: Hesham Masoud, MD, Boston Medical Center, FGH Building, 3rd Floor, Boston, MA 02118; email: email@example.com
Intracranial atherosclerotic disease is an important etiology of stroke and accounts for 10-15% of all ischemic strokes. The mechanism of stroke is attributed to thrombus formation at the site of stenosis with distal embolization, or hemodynamic flow reduction to areas with poor collateral circulation. Plaque rupture can initiate a cascade resulting in thrombus formation and subsequent occlusion of the stenotic artery and its perforator branches. Uncertainty regarding antithrombotic therapy led to the WASID trial; a comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. This randomized, double blinded, multicenter study comparing medical therapy in the management of intracranial atherosclerotic disease in patients with 50-99% symptomatic stenosis revealed that an important factor predictive of stroke in the stenotic artery was stenosis measuring 70-99%; with stroke rates of 18% at 1 year (compared with 6% in patients with <70% stenosis). Given this significantly higher risk, it was hypothesized that these patients may be most suitable for endovascular management. The SAMMPRIS trial was conducted to determine whether intracranial stenting had additional benefit over intensive medical management in preventing a second stroke in high risk patients with symptomatic stenosis of a major intracranial artery. In this article, a brief overview of the SAMMPRIS trial and a literary review of its analysis is provided. The effect of the trial results on the proposed medical management of ICAD and alternatives to stenting are explored.
Key words: SAMMPRIS, ICAD, angioplasty, stenting
Intracranial atherosclerotic disease (ICAD) is one of the important etiologies of stroke, likely accounting for 10-15% of all ischemic strokes with increased incidence seen in certain populations (1). The mechanisms of stroke in ICAD are thrombus formation at the site of stenosis with distal embolization, or hemodynamic flow reduction to areas with poor collateral circulation. Plaque rupture can also initiate a cascade resulting in thrombus formation and subsequent occlusion of the stenotic artery and its perforator branches (2). Uncertainty regarding antithrombotic therapy for the treatment of ICAD led to the WASID trial; a comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. This randomized, double blinded, multicenter study comparing medical therapy in the management of ICAD in patients with 50-99% symptomatic stenosis revealed that an important factor predictive of stroke in the stenotic artery was stenosis measuring 70-99%; with stroke rates of 18% at 1 year (compared with 6% in patients with <70% stenosis)(3). Furthermore, strokes in the area of the stenotic artery were non-lacunar and often disabling (4). Time from qualifying event to enrollment was also a powerful predictor of recurrent stroke, especially in patients with 70-99% stenosis. In 132 patients with 70-99% stenosis that had their qualifying event within 30 days before enrollment, the 1 year stroke rate in the territory was 22.9% (compared to 9% in those with a qualifying event more than 30 days before enrollment) (3). Given this significantly higher risk, it was thought that these patients may be most suitable for endovascular management (5). In this article, a brief overview of the SAMMPRIS trial and a literary review of its analysis is provided. The effect of the trial results on the proposed medical management of ICAD and alternatives to stenting are explored.
The SAMMPRIS Trial
The SAMMPRIS trial was an investigator initiated, randomized, prospective, blinded trial of percutaneous transarterial angioplasty and stenting (PTAS) and aggressive medical management versus aggressive medical management alone conducted at 50 sites in the United States. The primary outcome measure was to determine whether intracranial stenting had additional benefit over intensive medical management in preventing a second stroke in high risk patients with symptomatic stenosis of a major intracranial artery. Funding was provided by the National Institute Health and supplementary funding for the study devices was provided by Stryker Neurovascular (5).
The main inclusion criteria for enrollment into the SAMMPRIS study required patients to have had a TIA or nondisabling stroke within 30 days prior to enrollment, attributed to a verified stenosis of 70 to 90% of the diameter of a major intracranial artery (internal carotid, M1 segment of middle cerebral artery, vertebral or basilar). The planned target sample size was to enroll a total of 764 patients (382 patients in each group) to achieve 80% power to show a relative reduction of 35% with PTAS in the risk of the primary end point. The primary end point was defined as stroke or death within 30 days after enrollment or after revascularization procedure for the qualifying lesion during the follow up period or stroke in the territory of the qualifying artery beyond 30 days.
Medical management in the two groups was identical. Both arms received aspirin 325 mg and clopidogrel 75 mg daily for 90 days after enrollment. Primary vascular risk factors were managed closely (target systolic blood pressure < 140 mm Hg and in patients with diabetes, < 130 mm Hg; LDL cholesterol level of < 70 mg/dl) and secondary risk factors were manged with INTERxVENT USA, a lifestyle modification program. The study provided patients with aspirin, clopidogrel, one drug from each major class of antihypertensive agents and rosuvastatin.
The patients randomized to PTAS were required to undergo the procedure within 3 days of randomization. PTAS was performed using the Gateway PTA Balloon Catheter and Wingspan Stent System. Intravenous heparin was administered during the procedure to achieve an activated clotting time between 250 and 300 seconds. Patients not on daily clopidogrel for 5 days before PTAS were given a 600 mg loading dose between 6 and 24 hours before the procedure (5).
Randomization began in November 2008 and two interim efficacy analyses were planned when approximately 33% and 66% of the required end points had occurred. In April 2011 enrollment was stopped at 451 patients per the recommendation of the study independent data and monitoring board (6).
Of the 451 patients who underwent randomization, 227 were assigned to the medical-management group and 224 to the PTAS group. There were no significant differences regarding patients’ baseline characteristics. The study results demonstrated a higher than expected 30 day stroke rate in the patients treated with stent plus medical therapy and a lower than expected 30 day stroke rate with medical therapy alone. The probability of the primary end point within 30 days was 14.7 % in the PTAS group and 5.8% in the medical-management group. Beyond 30 days, ischemic stroke in the territory of the qualifying artery occurred in 13 patients for each group. The 1 year stroke rate was 20% and 12.2% in the PTAS and medical-management groups respectively (although fewer than half of the patients have reached the 1 year point)(6).
Medical Management of ICAD
There have been several trials (7-9) that have compared aspirin with other antithrombotic agents in the prevention of strokes, however the proportion of patients with ICAD was not specified. The WASID trial helped define the use of anticoagulant and antithrombotic medications in the treatment of ICAD, revealing that warfarin provided no benefit over aspirin and was associated with higher rates of adverse events. A general recommendation in favor of treatment with aspirin over warfarin was established for the management of ICAD (3). The SAMMPRIS trial used the most common practice amongst interventionalists surveyed coupled with information from the CHARISMA and MATCH trials (10, 11) (suggesting an improvement in stroke risk without increased risk of intracranial hemorrhage when using dual antithrombotic therapy for 90 days) to come up with the medical regimen in their study (5). The results of the SAMMPRIS study demonstrate that this may be a very effective strategy for the treatment of severe ICAD and has since been recommended as standard of practice (12).
A recent prospective study of 22 patients who failed to qualify or declined to participate in SAMMPRIS showed that dual antiplatelet therapy with aspirin and clopidogrel combined was effective for the prevention of recurrent vascular events. In this study the early aggressive management protocol was modeled after the intensive medical therapy arm of SAMMPRIS with the exception that their cohort was continued on dual antiplatelet therapy beyond 3 months (13).
SAMMPRIS is the first study to specifically address vascular risk factors and lifestyle modification in patients with ICAD. The trial results confirm the importance of intensive management of other atherosclerotic risk factors, especially smoking cessation, physical activity, lowering blood pressure and LDL cholesterol to achieve target levels delineated in the study protocol and based on national standards (5). There has been concern about the uncertainty of being able to duplicate the aggressiveness of the prescribed risk management regimen and life style modification seen in SAMMPRIS into a “real world” practice setting (14). Note that even in the WASID trial few patients achieved the target blood pressure and LDL values (50% and 63% at 1 year of follow up respectively) (15). The SAMMPRIS trial results however give providers motivation that these goals can be met and high risk patients can significantly benefit from such an aggressive regimen. The INTERxVENT program provided services to help achieve these goals and proved highly effective, which suggests the significant value of these services. However most insurers do not reimburse for these private services and many patients are unable to afford it on their own. Perhaps this should be reconsidered and become standard medical practice or primary care providers and neurologists should allocate more time to optimizing every vascular risk factor in patients with ICAD (16). The medical therapy treatment with the SAMMPRIS regimen had not been proven in a randomized trial, nor was this regimen standard of practice prior to the publication of the SAMMPRIS results (12).
Analysis of SAMMPRIS
In SAMMPRIS the difference between the treatment groups in the rate of the primary end point was driven by the early events, since the rates beyond 30 days were similar in the two groups (6). This points to the importance of patient selection for acute endovascular intervention and the importance of optimizing procedural safety. Enrollment in SAMMPRIS did not require a failure of medical therapy with 38% of patients enrolled in the medical arm and more than 35% of those in the stenting arm, not having been on antithrombotic medications at the time of their qualifying event (6). Now that failure of medical therapy has been redefined, the future endovascular approaches for treatment of ICAD will need to focus on those subgroups of patients in SAMMPRIS that continued to have a high risk of stroke despite aggressive medical therapy (17). In the GESICA study (a prospective study of symptomatic atherothrombotic intracranial stenosis), 27.4% of the patients studied had stenosis with clinically hemodynamic characteristics (flow limiting, critical intracranial arterial stenosis), 60.7% of which suffered a recurrent ischemic stroke or TIA in the territory of the stenotic artery (18). Recurring ischemic symptoms among patients with this kind of stenosis usually necessitate early or urgent treatment, as such most of these patients are unable to wait a week or more for treatment (19). In the SAMMPRIS study the median time from stroke to enrollment was 7 days, as such it is possible that many patients with active hemodynamic failure were not considered to be a candidate for inclusion in SAMMPRIS (16). Perhaps those patients with hemodynamic stenosis that have failed optimal medical therapy may be the most suited for enrollment in the next study of ICAD endovascular intervention, though these numbers will be likely small.
A total of 33 periprocedural strokes (14.7%) occurred among the 224 patients assigned to the PTAS arm in the SAMMPRIS study (6). In an analysis of factors affecting periprocedural stroke, it was noted that 3 ischemic stroke events occurred in patients where PTAS was not performed due to findings on angiography at the time of PTAS (stenosis < 50% in one, complete occlusion on angiography in two), leading to the total periprocedural strokes counted in the analysis as 30 (19 ischemic and 11 hemorrhagic strokes) (20). Periprocedural strokes seen in SAMMPRIS had multiple causes with perforator occlusion being the most common cause of ischemic stroke (n=12/19) and hemorrhagic stroke nearly evenly divided between SAH (n=5/11) and reperfusion hemorrhage (n=6/11) (20).
The factors associated with hemorrhagic stroke were higher percentage stenosis, low mRS and clopidogrel load associated with intraprocedural activated clotting time greater than 300 seconds. Higher percentage stenosis may be at higher risk for perforation due to increased difficulty of crossing the stenosis with a microwire. The higher grade stenosis may also be associated with more severe hemodynamic impairment, increasing the risk of reperfusion injury when flow is restored. The risk of hemorrhage with clopidogrel load and increased ACT stresses the importance of maintaining ACT in target range throughout the procedure (although this may be difficult; in SAMMPRIS this was only achieved in 50% of the PTAS patients) (20). It is unclear why an association with low mRS was found and this may represent a Type I error.
Fiorella et al. noted that patients who presented with perforator territory stroke did not translate to perforator type stroke after PTAS. The perforator strokes recorded after PTAS were seen after basilar PTAS, which may be the result of atherosclerotic debris being displaced or “snowplowed” over the perforator origins during angioplasty or stent deployment. However the perforator rich middle cerebral artery was associated with the lowest rate of periprocedural ischemic stroke of all arteries in the trial (20).
Theoretically, placement of stents may be more damaging to the diseased vessel; primary stenting may release plaque into the distal cerebral vessels through embolization or “cheese grating” of the stent deployment on the atherosclerotic plaque (21).
Due to the unanticipated increased periprocedural risk with PTAS seen in SAMMPRIS, alternative endovascular approaches for the treatment of ICAD have been discussed. Specifically, balloon angioplasty has been proposed as a treatment that may allow for revascularization of the affected vascular territory with a less traumatic intervention than stenting (21).
The technique of submaximal angioplasty, where the balloon is undersized relative to the target vessel, appears to have a reasonable complication rate. Potential benefits of limited trauma to the intracranial plaque and partial recanalization may reduce the risk of ischemic stroke and reperfusion hemorrhage. A recent retrospective review of 41 consecutive cases demonstrated the periprocedural safety of submaximal angioplasty with a morbidity of 4.9%. In addition, the 1 year perioperative event and ischemic event free survival rate (91%) compared favorably with rates in the medical arm (88%) and stenting arm (77%) of SAMMPRIS (21). Similar larger studies of angioplasty alone reported 30 day stroke or mortality rates of 4.8%-8% (22-25).
After the results of SAMMPRIS were published, the FDA issued a communication to inform health care providers and patients that they were narrowing the indications for use of the Wingspan stent in ICAD. This was based on analysis of the original HDE clinical study in addition to data since the device was approved and data from the SAMMPRIS trial. The FDA has delineated a specific group of patients that may benefit from the Wingspan device.
Currently, Wingspan is approved for patients who are between 22 and 80 years old who meet all of the following criteria: two or more strokes despite aggressive medical management; most recent stroke occurring more than seven days prior to planned treatment with Wingspan; 70-99 percent stenosis due to atherosclerosis of the intracranial artery related to the recurrent strokes; and those who have made good recovery from previous stroke (modified Rankin score of 3 or less) prior to Wingspan treatment.
Furthermore, the FDA states that the Wingspan device is not to be used for the treatment of stroke with an onset of symptoms within seven days or less of treatment; or for the treatment of transient ischemic attacks (TIAs).
The FDA plans on continued evaluation and monitoring of adverse events related to the Wingspan device. The agency will also monitor the results of ongoing follow up of the SAMMPRIS patients. In addition, the FDA is requiring Stryker to conduct a post-market study (26).
While the results of SAMMPRIS were met with some disappointment from the neurointerventional community, it is important to recognize that it represents a landmark study for the fields of interventional neuroradiology and vascular neurology. SAMMPRIS is the only large prospective cohort of patients undergoing PTAS for ICAD at multiple sites by credentialed interventionalists, with all end points evaluated by site neurologists and central blinded adjudicators, thus providing us with unique information regarding the technical success of PTAS as well as the etiology and risk factors for procedural cerebrovascular complications (20).
Although the estimated total 1 year stroke rate of 12.2% (6% within the first 30 days) in the medically treated arm was below expected, it still represents a significant risk. The results of the trial, while providing useful information regarding the efficacy of an aggressive medical regimen, should not represent an obstacle for the development of new catheter based treatments for symptomatic ICAD. We are aware from experience with the innovations seen in endovascular aneurysm therapy that evolution of neurointerventional devices can lead to improved treatment effectiveness and improved patient outcomes (14). SAMMPRIS has showed that employing an aggressive medical regimen can be very effective in treating patients with severe ICAD. Regarding endovascular therapy, the results of the trial suggest that this may be best reserved for patients who have persistent events refractory to a medical regimen similar to that employed in SAMMPRIS. Further study is needed to identify this subgroup before a clinical trial can demonstrate the benefit of endovascular therapy in the treatment of severe ICAD.
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