Atherosclerotic stenosis of intracranial arteries is an important cause of ischemic stroke, and the risk of stroke recurrence is very high in these patients, especially in severe stenosis of intracranial arteries (70%-99%), where the 1-year risk of stroke recurrence is still as high as 23% even after standardized medical treatment. In recent years, with the continuous progress of endovascular treatment, especially the introduction of percutaneous intracranial artery stenting and the design and development of specialized stents for intracranial stenosis (e.g., Wingspan et al.), the success rate of stenting techniques is increasing and its effectiveness and safety have been confirmed in small multicenter studies, but there is no high-level clinical evidence yet.
SAMMPRIS, the first international prospective multicenter randomized controlled trial comparing intensive medical therapy with intensive medical therapy + intracranial stent intervention for recurrent stroke prevention in patients with high-risk intracranial artery stenosis (70%-99%), was terminated prematurely in April this year because its mid-stage analysis suggested that intensive medical therapy was significantly better than intracranial stent placement.
This issue features Professor Jiao Liqun from Beijing Xuanwu Hospital, who provides insight into the SAMMPRIS study and tells us the story of intracranial stenting in China ……
Insights into the low incidence of stroke in the drug treatment group of the SAMMPRIS study
The WASID and SAMMPRIS studies used the same enrollment criteria and patients received aspirin or warfarin + standard risk factor control, but had significantly higher 30-day and 1-year stroke event and mortality rates. the SAMMPRIS investigators concluded that the combination of aspirin and clopidogrel was key to a significant reduction in early stroke risk. The SAMMPRIS study suggests that: (1) lifestyle modification has little effect on short-term stroke risk reduction; (2) stricter control of low-density lipoprotein cholesterol (LDL-C) levels and systolic hypertension in patients in the SAMMPRIS study may also be one of the main reasons for fewer stroke events in the drug-treated group; and (3) significant differences in stroke event rates between the two groups occurred mainly within 30 days, and continued long-term follow-up is needed.
SAMMPRIS design flaws
The SAMMPRIS investigators explained the high stroke incidence and mortality in the intracranial artery stenting group by the following: (1) it was not related to the skill level of the interventionalists in the included centers, most of whom had relevant qualifications and some degree of clinical experience; (2) the included patients had symptomatic episodes within 30 days, excluding those with episodes longer than 30 days and moderate arterial stenosis (50%-69%).
In addition, although not reflected in the full SAMMPRIS study report, it is undeniable that approximately 1/3 of strokes in the intracranial arterial intervention group in that study were cerebral hemorrhages, which rarely occurred in the CREST study.
An analysis of the SAMMPRIS study report shows that the study has some shortcomings.
1. The included population had symptomatic episodes within 30 days
Recent symptomatic episodes suggest the presence of unstable plaque at the stenosis site and an increased risk of embolus dislodgement and distal vessel occlusion during stent placement. In addition, in recently symptomatic patients, fresh infarct areas can be detected by cranial magnetic resonance imaging (MRI), and stent placement improves perfusion and increases the risk of ischemia-reperfusion. All of these factors increase the incidence of stroke.
2. Single stent only
Only one stent system, the Wingspan self-expanding stent release system, was used in the SAMMPRIS study. It is not known whether other types of stents are safer and more effective than the Wingspan stent.
In addition, the study failed to give data related to balloon dilation alone. It has been emphasized that the U.S. Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS) played a very important regulatory role in the study. 2005, the FDA approved the Wingspan stent for clinical use, and in 2008, the SAMMPRIS study was conducted with some funding. However, CMS does not pay for stents outside of clinical trials. This policy is closely related to the successful completion of the study, and the FDA and CMS should “level the playing field” in the use of stent technology, so that more new technologies can be used in clinical trials for the benefit of more patients.
3. The relationship between long-term and short-term efficacy
From the WASID study, the risk of stroke recurrence was highest within 2 months after the first onset of symptoms, but the rate of recurrence of adverse events remained high in the following 1 and 2 years. Therefore, for stroke prevention, both drugs and stents should be focused on both short and long term.
In the SAMMPRIS study, the difference in adverse event rates was significant at 30 days (5.8% in the drug group versus 14.7% in the stenting group), but there was no difference between 30 days and 1 year (5.7% in the drug group versus 5.8% in the stenting group); is it possible that stenting is more effective than drug therapy at 2 years postoperatively? Unfortunately, the 1-year postoperative follow-up data is less than half of the sample size, and there is no longer-term follow-up data, which leaves another question.
4. Strict system of stroke definition
In the SAMMPRIS study, a more rigorous evaluation method was used to define stroke events, including neurologists’ evaluation, judgment, confirmation and follow-up of all possible observed endpoints, which may have improved stroke detection rates, including some minor strokes with mild symptoms. For example, the proportion of disabling/fatal strokes in the primary endpoint in the intracranial stenting group was 35% (16 cases/46 cases), which is significantly higher than previous data (21%) or recent data from randomized controlled studies of carotid endarterectomy (CEA) (28%).
5. Mismatch between the two group designs
In the SAMMPRIS study, the mismatch between the two groups involved mainly the use of clopidogrel, which was applied more often in the stent placement group with clopidogrel 600
In the SAMMPRIS study, the mismatch between the two groups was mainly related to the use of clopidogrel, which was more frequently used in the stent placement group than clopidogrel 600 mg as a preoperative drug.
6. Differentiation of high-risk groups for stroke
The GESICA study suggests that not all patients with intracranial artery stenosis are at high risk, and that the recurrence rate of stroke or transient ischemic attack (TIA) can be as high as 61% in patients with hemodynamic impairment and 38% in patients without hemodynamic impairment. Therefore, patients with intracranial artery stenosis should be distinguished from those at high risk for stroke, who may be more suitable for intracranial stenting.
7. Interventional physician skill and experience
Although the authors of the SAMMPRIS study emphasized the qualifications of the centers and physicians participating in the study, only 200 stenting treatments were completed at 50 centers during the 29-month study period, an average of less than 2 cases per center in 1 year. Even with the qualification requirements for both physicians and hospitals, such a volume of treatment really does not guarantee continued skill level of physicians.
Also, about 1/3 of strokes in the stent placement group are hemorrhagic strokes. The usual cause of cerebral hemorrhage after stent placement is reperfusion injury or subarachnoid hemorrhage due to operation-related vascular injury. Although the authors did not specifically analyze the cause of this complication, they again emphasized that intracranial stenting techniques are more risky than extracranial. It is not surprising that the safety of intracranial stent placement in this study is significantly worse than the numbers reported in previous literature.