CASSISS
Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis
Year of Publication: 2022
Authors: Peng Gao, Tao Wang, Daming Wang, ..., for the CASSISS Trial Investigators
Journal: JAMA
Citation: JAMA. 2022;328(6):534-542.
Link: https://jamanetwork.com/journals/jama/fullarticle/2795086
PDF: Clinical Question
Among patients with TIA or nondisabling ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, does percutaneous transluminal angioplasty and stenting (performed ≥3 weeks after the index event) plus medical therapy reduce the risk of stroke or death compared with medical therapy alone?
Bottom Line
Adding PTAS (Wingspan stent) to medical therapy did not reduce the 1-year risk of stroke or death compared with medical therapy alone (8.0% vs 7.2%; HR 1.10; 95% CI 0.52-2.35; P=0.82). No differences at 2 or 3 years. The 30-day periprocedural stroke/death rate was 5.1% (stenting) vs 2.2% (medical), and 3-year mortality was numerically higher with stenting (4.4% vs 1.3%; HR 3.75; P=0.08).
Major Points
- No benefit of stenting: primary composite (stroke/death ≤30 days or qualifying-territory stroke through 1 year) was 8.0% (stenting) vs 7.2% (medical), HR 1.10 (95% CI 0.52-2.35; P=0.82).
- Higher 30-day periprocedural risk: 5.1% (9/176) stenting vs 2.2% (4/181) medical — more than double.
- sICH only in stenting group: 4 patients (2.3%) within 30 days, 2 were fatal (guidewire perforation). 0% in medical group.
- No difference at 2 or 3 years: territory stroke at 3 years was 11.3% vs 11.2% (HR 1.00; P>.99).
- Numerically higher mortality with stenting: 3-year death 4.4% (7/160) vs 1.3% (2/159), HR 3.75 (95% CI 0.77-18.13; P=0.08).
- Refined selection did NOT help: excluded perforator strokes, required ≥3 weeks from event, credentialed high-volume sites (>30 cases/year, <15% complication rate) — stenting still did not outperform medical therapy.
- Much lower event rates than SAMMPRIS: 1-year primary 8.0%/7.2% vs SAMMPRIS 20%/12.2%, likely due to longer event-to-enrollment interval (median 35 vs 7 days) and exclusion of perforator strokes.
- Predominantly Chinese Han population (98%), mean age 56 years — much younger than SAMMPRIS (60) and VISSIT (62). Generalizability uncertain.
- Only Wingspan stent evaluated; drug-coated balloons and drug-eluting stents not tested.
- Large screened-to-enrolled ratio: 1,152 screened, 380 randomized (33%), 222 excluded for unfavorable anatomy.
Design
Study Type: Multicenter, open-label, randomized, outcome assessor-blinded trial
Randomization: 1
Blinding: Open-label; independent outcome committee and imaging core laboratory blinded to treatment assignment. Simple 1:1 randomization without blocking or stratification via Interactive Voice Response System.
Enrollment Period: March 5, 2014 to November 10, 2016
Follow-up Duration: 3 years (final follow-up November 10, 2019). Regular follow-up at 1 month, 1, 2, and 3 years.
Centers: 8
Countries: China
Sample Size: 358
Analysis: Full analysis set (FAS) as primary (all eligible randomized); per-protocol set (PPS) as secondary. Cox proportional hazards adjusting for center. Competing risk models for select outcomes.
Inclusion Criteria
- TIA (WHO: acute neurologic deficit <24h) or nondisabling ischemic stroke (persisting >24h, confirmed on DWI) with mRS 0-2.
- Severe stenosis (70-99%) of a major intracranial artery supplying the ischemic territory, confirmed by conventional angiography using WASID criteria.
- Qualifying event beyond 3 weeks from the latest ischemic symptom onset to enrollment (patients with TIA/stroke within the last 3 weeks were excluded).
- Nonperforator territory stroke only (non-brainstem, non-basal ganglia end-artery territory).
- MRI (or CT if MRI contraindicated) to confirm criteria.
- Written informed consent.
- Site credentialing: ≥5 cases per surgeon during lead-in, annual volume >30, 30-day complication rate <15%.
Exclusion Criteria
- Prespecified unfavorable anatomical features or other intracranial diseases (n=222 excluded).
- Perforator stroke only or recent events ≤3 weeks prior (n=70).
- Previous endovascular treatment (n=69).
- Severe allergy to contrast or antiplatelet drugs or active bleeding diathesis (n=56).
- Psychiatric disorders, pregnancy, or involved in other trials (n=18).
- Comorbidities precluding general anesthesia or angiographic assessment (n=12).
- Concomitant extracranial stenosis.
Baseline Characteristics
| Characteristic | Stenting + Medical (N=176) | Medical Alone (N=182) |
|---|---|---|
| Age (mean±SD) | 56.7±9.4 | 55.9±9.8 |
| Male sex | 128 (72.7%) | 135 (74.2%) |
| Hypertension | 117 (66.5%) | 125 (68.7%) |
| Diabetes | 57 (32.4%) | 44 (24.2%) |
| Coronary artery disease | 19 (10.8%) | 19 (10.4%) |
| Lipid disorder | 18 (10.2%) | 21 (11.5%) |
| Current smoker | 41 (23.3%) | 50 (27.5%) |
| Qualifying event — TIA | 87 (49.4%) | 77 (42.3%) |
| Qualifying event — Stroke | 89 (50.6%) | 105 (57.7%) |
| Stroke mechanism — Artery-to-artery embolism | 57/89 (64.0%) | 58/105 (55.2%) |
| Stroke mechanism — Isolated hypoperfusion | 18/89 (20.2%) | 22/105 (21.0%) |
| Stroke mechanism — Mixed | 14/89 (15.7%) | 25/105 (23.8%) |
| Time event to randomization (median, IQR) | 34.5 (27.0-65.5) days | 36.0 (28.0-68.0) days |
| Symptomatic artery — MCA M1 | 65 (36.9%) | 79 (43.4%) |
| Symptomatic artery — Basilar | 50 (28.4%) | 52 (28.6%) |
| Symptomatic artery — Intracranial VA | 46 (26.1%) | 34 (18.7%) |
| Symptomatic artery — Intracranial ICA | 15 (8.5%) | 17 (9.3%) |
| Stenosis degree (median, IQR) | 78.5% (74.1-82.6) | 76.6% (73.2-80.9) |
| Stenosis 70-79% | 105 (59.7%) | 130 (71.4%) |
| Stenosis 80-89% | 65 (36.9%) | 46 (25.3%) |
| Stenosis 90-99% | 6 (3.4%) | 6 (3.3%) |
| NIHSS (median, IQR) | 0.0 (0.0-1.0) | 0.0 (0.0-0.0) |
| mRS (median, IQR) | 0.0 (0.0-1.0) | 0.0 (0.0-1.0) |
| Prior antiplatelet therapy | 49 (27.8%) | 48 (26.4%) |
| Prior statin therapy | 19 (10.8%) | 20 (11.0%) |
Arms
| Field | Stenting + Medical Therapy | Control |
|---|---|---|
| Intervention | Percutaneous transluminal angioplasty and stenting with Wingspan stent (Stryker Neurovascular) under general anesthesia, performed within 3-5 days of randomization. No loading dose of aspirin or clopidogrel before procedure. Same medical therapy as control arm started immediately after randomization. | Aspirin 100 mg daily + clopidogrel 75 mg daily for 90 days (then single antiplatelet). Risk factor targets: LDL <2.58 mmol/L (100 mg/dL) with statins; SBP <140 mmHg (<130 mmHg if diabetic), DBP <90 mmHg. Per 2014 AHA/ASA guidelines. |
| Duration | Stenting is a one-time procedure + ongoing medical therapy for 3 years | 3 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of stroke or death within 30 days, or stroke in territory of qualifying artery beyond 30 days through 1 year | Primary | 13/181 (7.2%) | 14/176 (8.0%) | 1.1 | 0.82 |
| Stroke or death ≤30 days (component) | Secondary | 4/181 (2.2%) | 9/176 (5.1%) | ||
| Territory stroke >30 days through 1 year (component) | Secondary | 9/181 (5.0%) | 5/176 (2.8%) | ||
| Stroke in same territory within 2 years | Secondary | 16/178 (9.0%) | 17/171 (9.9%) | HR 1.10 | 0.80 |
| Stroke in same territory within 3 years | Secondary | 19/170 (11.2%) | 19/168 (11.3%) | HR 1.00 | >0.99 |
| Disabling stroke or death within 3 years | Secondary | 15/166 (9.0%) | 19/168 (11.3%) | HR 1.28 | 0.49 |
| Any stroke/TIA/CV events within 3 years | Secondary | 31/172 (18.0%) | 24/169 (14.2%) | HR 0.76 | 0.31 |
| Death within 3 years | Secondary | 2/159 (1.3%) | 7/160 (4.4%) | HR 3.75 | 0.08 |
| 30-day stroke or death — Stenting | Adverse | 4/181 (2.2%) | 9/176 (5.1%) | ||
| sICH within 30 days | Adverse | 0/182 (0%) | 4/176 (2.3%) | ||
| 30-day ischemic stroke — Stenting | Adverse | 4 (all ischemic) | 5 ischemic strokes (5 disabling) | ||
| 30-day hemorrhagic stroke — Stenting | Adverse | 0 | 4 hemorrhagic (2 fatal: guidewire perforation) | ||
| 3-year all-cause death | Adverse | 2/159 (1.3%): 1 ischemic stroke, 1 brain hemorrhage | 7/160 (4.4%): 2 brain hemorrhage, 2 ischemic stroke, 1 sudden cardiac arrest, 1 intrahepatic cholangiocarcinoma, 1 aortic artery aneurysm |
Subgroup Analysis
Post hoc by qualifying event: ischemic stroke subgroup — 10.1% (9/89) stenting vs 8.6% (9/105) medical; TIA subgroup — 5.7% (5/87) stenting vs 5.3% (4/76) medical. No interaction p-values reported.
Criticisms
- Only Wingspan stent evaluated; drug-coated balloons, drug-eluting stents, and angioplasty alone not tested.
- Conducted only in Chinese centers — generalizability uncertain. Han ethnicity 98%.
- Enrolled 2014-2016 — management changes since then may limit applicability.
- Medical management may not have been as aggressive as SAMMPRIS (LDL target <100 mg/dL vs SAMMPRIS <70 mg/dL).
- Lower than expected event rates (7.2% medical vs assumed 18%) — study likely underpowered.
- Open-label design (mitigated by blinded adjudication).
- Nonnegligible periprocedural complications: 2.3% sICH, 2 fatal hemorrhages from guidewire perforation.
- Large screened-to-enrolled ratio (33%) with 222 excluded for anatomy — highly selected population.
- Numerically higher 3-year mortality with stenting (4.4% vs 1.3%) is concerning though not significant.
Funding
National Health Commission of the People's Republic of China (2011BAI08B04). Stryker Neurovascular provided supplemental funding for third-party site monitoring and auditing. Funders had no role in design, conduct, analysis, or manuscript decisions.
Based on: CASSISS (JAMA, 2022)
Authors: Peng Gao, Tao Wang, Daming Wang, ..., for the CASSISS Trial Investigators
Citation: JAMA. 2022;328(6):534-542.
Content summarized and formatted by NeuroTrials.ai.