Intracranial Atherosclerotic Disease (ICAD)

Intracranial atherosclerotic disease (ICAD) accounts for 8-10% of ischemic strokes in Western populations and up to 30-50% in Asian and Hispanic populations, making it one of the most common stroke etiologies worldwide. Patients with symptomatic severe ICAD face a 12-20% annual risk of recurrent stroke — among the highest of any stroke subtype.

The history of ICAD treatment is one of repeated interventional failures and the triumph of aggressive medical therapy. Despite intuitive appeal, intracranial stenting has consistently failed to improve outcomes over medical management alone. The landmark SAMMPRIS trial in 2011 not only stopped the momentum toward routine stenting but also established a rigorous medical regimen that remains the standard of care today.

Pathophysiology and Risk Stratification

Stroke in ICAD occurs through multiple mechanisms: artery-to-artery thromboembolism from unstable plaque, hypoperfusion due to flow-limiting stenosis, branch vessel (perforator) occlusion by plaque extension, or a combination of these. Understanding the dominant mechanism in an individual patient can inform treatment decisions — hypoperfusion may warrant more aggressive revascularization consideration, while embolic mechanisms respond well to antithrombotic optimization.

High-Risk Features

Not all ICAD carries the same recurrence risk. Factors associated with higher stroke recurrence include:

• Severe stenosis (≥70%) — highest risk category in WASID and SAMMPRIS
• Recent symptoms (<30 days) — early recurrence risk is highest
• Poor collateral circulation — hemodynamic vulnerability
• Diabetes mellitus — independent predictor of recurrence
• Progressive stenosis on follow-up imaging
• Multiple risk factors poorly controlled at baseline

Medical Therapy: The SAMMPRIS Protocol

The medical arm of SAMMPRIS achieved remarkably low stroke rates — only 12.2% at 1 year — far better than historical controls (~20%). This "aggressive medical management" protocol has become the template for ICAD treatment.

The Stenting Story: Why It Failed

The rationale for intracranial stenting was compelling: restore luminal diameter, improve flow, and prevent thromboembolism. Yet trial after trial has failed to demonstrate benefit — and most showed harm.

WASID (2005): Warfarin vs Aspirin

WASID randomized 569 patients with 50-99% symptomatic intracranial stenosis to warfarin (INR 2-3) versus aspirin 1300 mg daily. There was no difference in the primary endpoint (stroke, hemorrhage, or vascular death): 22.1% with aspirin vs 21.8% with warfarin. However, warfarin was associated with significantly higher rates of death (9.7% vs 4.3%, p=0.02) and major hemorrhage (8.3% vs 3.2%, p=0.01). The trial established aspirin as the preferred antithrombotic for ICAD.

SAMMPRIS (2011): The Definitive Trial

SAMMPRIS randomized 451 patients with 70-99% stenosis within 30 days of TIA or stroke to Wingspan stenting plus aggressive medical therapy versus aggressive medical therapy alone. The trial was stopped early for harm:

• 30-day stroke or death: 14.7% stenting vs 5.8% medical (p=0.002)
• 1-year primary endpoint: 20.0% stenting vs 12.2% medical (p=0.009)
• Periprocedural strokes were largely perforator infarcts

SAMMPRIS definitively showed that stenting confers early harm without long-term benefit, even in the highest-risk patients.

VISSIT (2015): Balloon-Expandable Stents

VISSIT tested balloon-expandable stents (rather than self-expanding Wingspan) in 112 patients with 70-99% stenosis. Results were even worse: 1-year stroke rate was 36% with stenting versus 15% with medical therapy. The trial confirmed that the problem was not the stent type — it was the concept of elective intracranial stenting itself.

CASSISS (2022): Delayed Intervention

CASSISS attempted to improve on SAMMPRIS by enrolling patients ≥3 weeks from their qualifying event (allowing the acute high-risk period to pass) and using experienced Chinese operators. Among 358 patients with 70-99% stenosis:

• 1-year primary endpoint: 8.0% stenting vs 7.2% medical (HR 1.10, p=0.82)
• 3-year stroke: 11.3% vs 11.2% (identical)

Even with delayed intervention and lower periprocedural complication rates, stenting provided no advantage over medical therapy.

WEAVE (2019): On-Label Safety

WEAVE was a single-arm post-market surveillance study of Wingspan stenting under strict FDA on-label criteria: 70-99% stenosis, ≥2 prior strokes (at least one on medical therapy), stenting ≥8 days from last stroke, experienced operators. Among 152 patients, the 72-hour stroke/death rate was only 2.6% — demonstrating that periprocedural risk can be minimized with careful patient selection. However, WEAVE was not a comparative trial and does not prove superiority over medical therapy.

Vertebral Artery Disease

Vertebral artery stenosis presents unique challenges. The vertebral arteries have both extracranial (V1-V3) and intracranial (V4) segments, with different risk profiles for intervention.

VAST (2015)

VAST randomized 115 patients with symptomatic vertebral artery stenosis (>50%) to stenting versus medical therapy. Stenting was associated with higher periprocedural complications and did not improve outcomes: 3-year stroke in vertebral territory was 12% with stenting versus 7% with medical therapy.

VIST (2019)

VIST randomized 182 patients with symptomatic vertebral stenosis (≥50%) to stenting plus best medical therapy versus best medical therapy alone. The trial was underpowered due to slow enrollment, but showed a trend favoring stenting (HR 0.40 for stroke, p=0.08). Notably, extracranial vertebral stenting had low periprocedural risk, while intracranial V4 stenting carried higher complication rates. Post-hoc analysis suggested potential benefit in patients randomized within 2 weeks of symptoms.

Clinical implication: Extracranial vertebral stenting may be safer than intracranial stenting, but medical therapy remains first-line. Stenting might be considered for highly selected patients with recurrent posterior circulation events despite optimal medical therapy.

Surgical Bypass: COSS and ERSIAS

COSS (2011): EC-IC Bypass Failed

COSS tested extracranial-intracranial (EC-IC) bypass surgery in patients with symptomatic carotid occlusion and hemodynamic compromise (elevated oxygen extraction fraction on PET imaging). Despite selecting the highest-risk hemodynamic patients, bypass did not reduce stroke:

• 2-year ipsilateral stroke or perioperative stroke/death: 21.0% surgery vs 22.7% medical (p=0.78)
• 30-day perioperative stroke: 14.3% surgery vs 2.0% medical

The high surgical complication rate negated any potential long-term benefit.

ERSIAS (2020): Indirect Bypass Shows Promise

ERSIAS tested encephaloduroarteriosynangiosis (EDAS) — an indirect bypass procedure that promotes neovascularization over time — combined with intensive medical management in 52 ICAD patients who had failed medical therapy. Results were encouraging:

• 2-year primary endpoint (stroke/death): 9.6% (vs 21.2% in propensity-matched controls)
• Functional independence: 86% at last follow-up
• Neovascularization: 89% demonstrated new vessel formation
• Surgical complications: Only 3.8%; no intracranial hemorrhages

ERSIAS phase II met criteria for advancement to phase III. EDAS may represent a safer surgical option for refractory ICAD by avoiding direct vessel manipulation.

The Acute Thrombectomy Exception: ANGEL-REBOOT

While elective stenting for chronic ICAD has failed, a different picture emerges in the acute thrombectomy setting. Many patients with large vessel occlusion have underlying ICAD as the culprit — and after thrombectomy, they may have residual high-grade stenosis or reocclusion.

ANGEL-REBOOT randomized 326 patients with failed thrombectomy (eTICI 0-2a) or high-grade residual stenosis (>70%) to bailout angioplasty or stenting (BAOS) versus standard therapy. One-year results showed significant benefit with BAOS:

• mRS 0-2 at 1 year: 67% BAOS vs 47% standard therapy (p<0.001)
• Stroke recurrence: 4% vs 13% (HR 0.30, p=0.006)
• Mortality: 15% vs 17% (NS)

Antithrombotic Therapy Beyond Standard DAPT

Given the limitations of intervention, research has focused on optimizing medical therapy beyond the standard SAMMPRIS regimen.

Cilostazol

Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet and vasodilatory properties, has shown favorable signals in Asian ICAD populations:

TOSS-2 (2011) compared cilostazol + aspirin versus clopidogrel + aspirin in 457 patients with symptomatic MCA or basilar stenosis. While not statistically significant, cilostazol showed favorable trends: stenosis progression 9.3% vs 15.5% (p=0.09), and fewer hemorrhagic complications. Cilostazol also improved lipid profiles (HDL, ApoB/ApoA1 ratio).

CATHARSIS (2015) compared cilostazol + aspirin versus aspirin alone in patients with intracranial stenosis. Again, favorable trends emerged: all vascular events 3.1% vs 7.4% (HR 0.39, p=0.09), stroke 2.5% vs 5.2% (p=0.19).

Clinical implication: Cilostazol may be considered as an adjunct or alternative to clopidogrel, particularly in Asian patients or those with clopidogrel resistance. Its favorable lipid effects and lower bleeding risk are additional advantages.

Low-Dose Anticoagulation: COMPASS-Like Regimens

Based on the success of the COMPASS trial in coronary artery disease, investigators are testing low-dose rivaroxaban (2.5 mg BID) plus aspirin in ICAD:

CATIS-ICAD Pilot (2015) randomized 110 patients to rivaroxaban 2.5 mg BID + aspirin versus aspirin alone. The composite endpoint (ischemic stroke or covert brain infarct) showed a promising signal: 15.7% vs 24.0% (HR 0.78, p=0.59) — not significant but underpowered. Importantly, there was no hemorrhagic stroke in either arm.

CATIS-ICAD Phase III is now enrolling to definitively test this regimen.

CAPTIVA is comparing three dual antithrombotic regimens head-to-head: ticagrelor + aspirin vs rivaroxaban 2.5 mg BID + aspirin vs clopidogrel + aspirin in 1,683 patients with 70-99% symptomatic ICAD. Results are pending.

Tirofiban: CHANCE-4

CHANCE-4 (2025) tested intravenous tirofiban in 4,724 patients with high-risk TIA or minor stroke due to intracranial atherosclerosis. The trial was neutral: recurrent stroke OR 1.00 (95% CI 0.83-1.22). Any bleeding was increased with tirofiban (3.8% vs 1.5%), though severe bleeding remained rare (0.4% vs 0.3%). Tirofiban does not appear to add benefit in this population.

Who Might Still Be Considered for Elective Intervention?

The role of elective endovascular therapy in ICAD is extremely limited and should be reserved only for highly selected patients at experienced centers.

Trial Comparison Tables

Antithrombotic Therapy Trials

Intracranial Stenting Trials

Vertebral Artery and Surgical Trials

References

1. Chimowitz MI, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis (WASID). N Engl J Med. 2005;352(13):1305-1316.
2. Chimowitz MI, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis (SAMMPRIS). N Engl J Med. 2011;365(11):993-1003.
3. Derdeyn CP, et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results. Lancet. 2014;383(9914):333-341.
4. Zaidat OO, et al. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis (VISSIT). JAMA. 2015;313(12):1240-1248.
5. Alexander MJ, et al. WEAVE Trial: final results in 152 on-label patients. Stroke. 2019;50(4):889-894.
6. Gao P, et al. Stenting plus medical therapy versus medical therapy alone for symptomatic intracranial stenosis (CASSISS). Lancet Neurol. 2022;21(3):227-236.
7. Kwon SU, et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis (TOSS-2). Stroke. 2011;42(12):3404-3411.
8. Han SW, et al. Cilostazol versus aspirin in ischemic stroke patients with intracranial symptomatic arterial stenosis (CATHARSIS). Ann Neurol. 2015;78(S19):S77.
9. Powers WJ, et al. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia (COSS). JAMA. 2011;306(18):1983-1992.
10. Gonzalez NR, et al. Encephaloduroarteriosynangiosis revascularization for symptomatic intracranial atherosclerotic disease (ERSIAS). Int J Stroke. 2021;16(5):534-544.
11. Markus HS, et al. Stenting for symptomatic vertebral artery stenosis (VIST). Lancet Neurol. 2019;18(7):666-673.
12. Zi W, et al. Bailout intracranial angioplasty or stenting after failed thrombectomy (ANGEL-REBOOT): 1-year outcomes. Stroke. 2025.