Past, Present, and Future of Intracranial Atherosclerosis Treatment

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Past, Present, and Future of Intracranial Atherosclerosis Treatment

Adam de Havenon and

Tanya N. Turan

Originally published28 Dec 2023https://doi.org/10.1161/STROKEAHA.123.044270Stroke. 2024;55:471–473

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Symptomatic intracranial atherosclerotic stenosis (sICAS), typically defined as an ischemic stroke or transient ischemic attack associated with a proximal 50% to 99% stenosis of a relevant intracranial artery, is one of the most common causes of ischemic stroke in the world.¹ Non-ICAS strokes have a first-year recurrence rate of 5%,² which is similar to the 1-year stroke rate in patients with asymptomatic severe ICAS.³ In clinical trials of sICAS, the 1-year recurrence rate has been ≈15%^4,5 and varies based on patient features such as degree of stenosis or history of prior stroke.^6,7 In real-world or enriched cohorts, it is even higher at 20% to 30% in the first year.⁸ Due to the high risk of recurrence, the randomized clinical trials (RCTs) in ICAS populations have focused on secondary prevention. In this article, we will review major RCTs in sICAS patients (Figure).

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Figure. Timeline of major randomized trials studying secondary prevention in individuals with symptomatic intracranial atherosclerotic stenosis. CAPTIVA indicates Comparison of Anti-Coagulation and Anti-Platelet Therapies for Intracranial Vascular Atherostenosis; EC/DC, extracranial/intracranial artery; RICA, Remote Ischemic Conditioning for Avoiding Recurrence of Symptomatic Intracranial Atherosclerotic Stenosis; SAMMPRIS, Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis; and WASID, Warfarin Aspirin Symptomatic Intracranial Disease.

The first RCT to include sICAS patients was the EC/IC Bypass Study ([International Cooperative Study of Extracranial/Intracranial Anastomosis]; n=1377), which tested surgical anastomosis from the superficial temporal artery to the middle cerebral artery among patients with stroke due to extracranial carotid occlusion or ICAS.⁹ One-quarter of the cohort qualified for enrollment with proximal middle cerebral artery stenosis or occlusion and, among those with ICAS, post hoc analyses showed an excessive periprocedural risk of stroke and death in the bypass group compared with the medical group, similar to the trial as a whole. Over a decade later, the WASID (Warfarin Aspirin Symptomatic Intracranial Disease; n=569) and subsequent SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis; n=451) RCTs studied therapeutic approaches used in practice (warfarin anticoagulation in WASID and angioplasty plus stenting in SAMMPRIS). Both studies changed the practice by identifying excessive adverse events due to these therapeutic approaches—hemorrhagic events in WASID and periprocedural stroke in SAMMPRIS.^4,5 Furthermore, in SAMMPRIS, even beyond the periprocedural period, there was no benefit of stenting over medical therapy after a mean follow-up of almost 3 years.¹⁰

SAMMPRIS was followed by 2 more angioplasty and stenting RCTs, VAST (Vertebral Artery Stenting Trial; n=115)¹¹ and VISSIT ([Vitesse Intracranial Stent Study for Ischemic Stroke Therapy]; n=112).¹² They also showed no benefit and, despite different stenting technology, the same harmful periprocedural risk. Almost a decade later, the results of another RCT, CASSIS ([China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis]; n=358), again showed no benefit from stenting in a sICAS population selected to be at lower procedural risk.¹³ The result of these RCTs is that intracranial stenting for stroke prevention in sICAS is recommended only as an option of last resort in treatment-refractory patients.^14–16 The treatment of sICAS with angioplasty alone is still an active area of investigation.

Yet, SAMMPRIS did establish a new paradigm for sICAS medical management. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was required for the first 90 days in SAMMPRIS. While this DAPT combination had demonstrated bleeding complications without clear benefit in the SPS3 (Secondary Prevention of Small Subcortical Strokes) and MATCH (Management of Atherothrombosis with Clopidogrel in High-Risk Patients) trials,^17,18 the lower than expected stroke rate in SAMMPRIS medical participants receiving DAPT led to guideline endorsement for DAPT for at least 90 days in sICAS.^14–16 SAMMPRIS also changed practice as the first stroke prevention trial to implement multimodal, protocol-driven intensive risk factor management and healthy lifestyle coaching. The impact from the vascular risk factor management approach used in SAMMPRIS, including targeted blood pressure and cholesterol management and lifestyle counseling, along with findings from other risk factor analyses of trials that included sICAS patients, demonstrated the importance of thinking beyond antithrombotic medications for stroke prevention.^14–16,19

Preliminary studies of remote ischemic conditioning suggested benefit in sICAS patients for stroke prevention,²⁰ potentially mediated by improved distal organ perfusion and lowering of systemic inflammation.²¹ This led to the RICA (Remote Ischemic Conditioning for Avoiding Recurrence of Symptomatic Intracranial Atherosclerotic Stenosis) RCT (n=3033),²² the largest sICAS secondary prevention trial to date. RICA was a sham-controlled RCT of a remote ischemic conditioning device placed on the upper arm for 45 min a day for over a year. Unfortunately, in both study groups of RICA, over 50% of participants had low compliance with the study protocol. The intervention appeared to numerically reduce recurrent strokes, particularly in the per-protocol analysis, but the results were not consistent with a meaningful treatment effect.

The largest current ongoing RCT in sICAS patients is CAPTIVA (Comparison of Anti-Coagulation and Anti-Platelet Therapies for Intracranial Vascular Atherostenosis),²³ which is a 3-arm, double-blind phase III trial comparing different antithrombotic combinations. CAPTIVA will randomize up to 1683 subjects with severe sICAS and recent stroke to 1 year of aspirin 81 mg combined with (1) ticagrelor (90 mg BID), (2) low-dose rivaroxaban (2.5 mg BID), or (3) clopidogrel (75 mg daily). All subjects will receive aggressive vascular risk factor management and the superior CAPTIVA arm at the end of the trial will likely set the new standard for sICAS secondary prevention.

Despite some progress in sICAS medical treatment over the years, the risk of stroke recurrence remains excessively high for symptomatic patients with severe stenosis. Prior studies have shown that the selection of low-risk patients with sICAS for therapeutic trials can improve adverse outcome rates but does not result in the practice-changing studies that are urgently needed.²⁴ Prioritized research areas for sICAS include exploring novel lipid-lowering therapies; anti-inflammatory medications; better understanding the interplay between plaque morphology, local and distal perfusion, and the success of treatment strategies; identifying genetic variants and surrogate markers that can inform new treatments and refine patient selection for future trials; improved revascularization technologies or techniques; and implementation science trials to pragmatically increase adherence to risk factor control. Although there is a wealth of research opportunities on the horizon, sICAS therapeutic trials must remain rigorous and focused on selecting patients at the highest risk of recurrent stroke who most need these novel treatments.