Neurology Clinical Trial Database
SAPPHIRE
Long-Term Results of Carotid Stenting versus Endarterectomy in High-Risk Patients
Year of Publication: 2008
Authors: Hitinder S. Gurm, M.D., Jay S. Yadav, ..., and Donald E. Cutlip
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2008;358:1572-9.
PDF: Clinical Question
In high-risk patients with severe carotid artery stenosis, what are the long-term (3-year) outcomes of carotid artery stenting with an emboli-protection device compared to carotid endarterectomy?
Bottom Line
In high-risk patients with severe carotid artery stenosis, there was no significant difference in the 3-year composite risk of death, stroke, or myocardial infarction between patients treated with carotid stenting with emboli protection and those who underwent carotid endarterectomy.
Major Points
- SAPPHIRE was the FIRST randomized trial to demonstrate noninferiority of carotid artery stenting (CAS) vs carotid endarterectomy (CEA) — published initially in 2004 (NEJM), with 3-year follow-up in 2008.
- Enrolled 334 HIGH-RISK surgical patients — those typically excluded from earlier CEA trials (NASCET, ECST). High-risk criteria: significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, recurrent stenosis, prior neck radiation, or age >80.
- 30-day primary composite (death, stroke, MI): 4.8% CAS vs 9.8% CEA (p=0.09) — stenting numerically favored, driven primarily by lower MI rates with CAS.
- 3-year composite (death, stroke, MI at 30 days + death or ipsilateral stroke at 31 days–3 years): 24.6% CAS vs 26.9% CEA (p=0.71) — no significant difference, confirming durability of noninferiority.
- The trial included a nonrandomized registry of 406 patients deemed too high-risk for one treatment — these had higher event rates, validating the high-risk classification.
- Used the Cordis PRECISE nitinol self-expanding stent with the Angioguard emboli-protection device — the FIRST trial to mandate distal embolic protection during CAS.
- Led directly to FDA approval of the Cordis stent system for high-risk patients in 2004 — transformed carotid revascularization practice.
- Criticized for industry sponsorship (Cordis) and the inclusion of MI in the primary endpoint, which favored stenting (MI more common with CEA due to general anesthesia/cardiac stress).
- Subsequent trials in AVERAGE-risk patients (CREST, ACT-1, SPACE, EVA-3S, ICSS) showed more nuanced results — CAS had higher stroke rates and CEA had higher MI rates, but long-term outcomes were similar.
- 3-year follow-up was incomplete in 22.2% of patients, raising concerns about ascertainment bias in the long-term results.
Design
Study Type: Prospective, randomized, multicenter trial.
Randomization: 1
Blinding: Unblinded (Open-label), typical for procedural trials.
Enrollment Period: Not stated in this 3-year follow-up publication.
Follow-up Duration: 3 years (1080 days).
Centers: 29
Countries: United States
Sample Size: 334
Analysis: Intention-to-treat.
Inclusion Criteria
- Patients at increased risk for complications from endarterectomy.
- Symptomatic carotid artery stenosis of at least 50% of the luminal diameter.
- OR asymptomatic stenosis of at least 80% of the luminal diameter.
- High-risk criteria included: clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis, previous radical neck surgery or radiation, or age >80 years.
Exclusion Criteria
- Intraluminal thrombus at the target lesion on preprocedural imaging.
- Total occlusion of the target carotid artery.
- Stroke-in-evolution or acute neurological deficit within 7 days (symptomatic patients required stability).
- Severe disability (mRS ≥3) from prior stroke in the territory of the target vessel.
- Contraindication to antiplatelet therapy (aspirin and/or clopidogrel allergy).
- Life expectancy <2 years due to severe comorbid illness.
- Known severe allergy to contrast media not amenable to premedication.
- Participation in another investigational drug or device trial.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Note | Not provided in 3-year follow-up manuscript; reported in prior publication | Not provided in 3-year follow-up manuscript; reported in prior publication |
Arms
| Field | Control | Carotid Artery Stenting |
|---|---|---|
| Intervention | Carotid endarterectomy performed according to the surgeon's preferred technique. | Carotid artery stenting with the use of a self-expanding nitinol stent and an emboli-protection device. Patients received clopidogrel before the procedure and for 2 to 4 weeks after. |
| Duration | One-time procedure | One-time procedure |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of death, stroke, or MI within 30 days or death/ipsilateral stroke 31 days-3 years | Primary | 26.9% (CEA) | 24.6% (CAS) | -2.3% | 0.71 |
| Death from any cause at 3 years | Secondary | 21.0% (CEA) | 18.6% (CAS) | 0.68 | |
| Any stroke at 3 years | Secondary | 9.0% (CEA) | 9.0% (CAS) | 0.99 | |
| Myocardial infarction at 3 years | Secondary | 8.4% (CEA) | 5.4% (CAS) | 0.39 | |
| Death at 1080 days | Adverse | 35/167 (21.0%) | 31/167 (18.6%) | 0.68 | |
| Stroke at 1080 days | Adverse | 15/167 (9.0%) | 15/167 (9.0%) | 0.99 | |
| Myocardial infarction at 1080 days | Adverse | 14/167 (8.4%) | 9/167 (5.4%) | 0.39 | |
| Neurologic cause death | Adverse | 4/167 (2.4%) | 3/167 (1.8%) | 0.99 | |
| Cardiac cause death | Adverse | 15/167 (9.0%) | 15/167 (9.0%) | 0.99 | |
| Target-vessel revascularization | Adverse | 9/167 (5.4%) | 4/167 (2.4%) | 0.26 | |
| Major ipsilateral stroke | Adverse | 5/167 (3.0%) | 2/167 (1.2%) | 0.45 | |
| Prespecified major adverse event composite at 3y | Adverse | 45/167 (26.9%) | 41/167 (24.6%) | 0.71 |
Criticisms
- Small randomized cohort (n=334) limits statistical power for subgroup analyses and increases susceptibility to type II error for individual endpoints.
- 22.2% of patients lost to follow-up at 3 years — this high attrition rate could introduce significant ascertainment bias, particularly if losses were differential between arms.
- Results apply ONLY to high-surgical-risk patients — cannot be extrapolated to average-risk patients (later addressed by CREST, ACT-1, SPACE, EVA-3S, ICSS).
- No medical-therapy-only arm — cannot determine whether either revascularization strategy is superior to modern optimal medical therapy alone (a question raised by CREST-2).
- Industry-sponsored (Cordis, the stent manufacturer) — potential for bias in trial design, conduct, and reporting. Cordis employees were involved in data analysis.
- Inclusion of MI in the primary composite endpoint favored CAS — MI was more common with CEA (due to general anesthesia, hemodynamic stress), inflating the apparent benefit of stenting.
- Embolic protection device (Angioguard) was first-generation — modern devices and stent designs have improved, making SAPPHIRE results less reflective of current CAS outcomes.
- The definition of 'high surgical risk' was broad and somewhat subjective — included heterogeneous conditions (cardiac disease, pulmonary disease, contralateral occlusion, prior neck surgery) that carry different risk profiles.
- Open-label design (inherent in procedural trials) introduces performance bias — surgeons and interventionalists may have managed patients differently based on treatment assignment.
Funding
Cordis
Based on: SAPPHIRE (The New England Journal of Medicine, 2008)
Authors: Hitinder S. Gurm, M.D., Jay S. Yadav, ..., and Donald E. Cutlip
Citation: N Engl J Med 2008;358:1572-9.
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