The SAPPHIRE trial enrolled patients with severe carotid-artery stenosis from 29 US centers. Eligible patients could be either asymptomatic with >80% stenosis by ultrasound or symptomatic with >50% stenosis and at least one feature that would make them high-risk: age greater than 80 years, the presence of congestive heart failure, severe COPD, previous endarterectomy with restenosis, previous radiation therapy or radical neck surgery, or lesions distal or proximal to the usual cervical location.

At the end of enrollment in June 2002, 406 patients had been included in the stenting registryconsidered by the surgeons as too high riskand a total of 334 patients were equally randomized to carotid stenting and carotid endarterectomy.

The primary end point of the study was the cumulative incidence of a major cardiovascular event at one yeara composite of death, stroke, or MI within 30 days after the intervention or death or ipsilateral stroke between 31 days and one year.

Yadav and colleagues note that while the statistical power of the study might have been enhanced with a larger sample, it met the intended primary noninferiority end point. A larger sample might have provided more support for the secondary finding of superiority of stenting, they write.

The rates of bleeding complications were similar in the two groups, but the rates of cranial-nerve palsy and revascularization, as well as the duration of hospital stay, were greater among those in the carotid endarterectomy group than among the stented patients.

In an editorial accompanying the published results, Dr Richard Cambria (Massachusetts General Hospital, Boston) calls SAPPHIRE an important study.2 Despite the impressive results, he argues, large multicenter trials are still needed to "clarify the appropriate role of carotid-artery stenting in patients in different clinical and anatomical subgroups." He adds that the safety and efficacy data from earlier clinical trials of endarterectomy established "an enviable standard for comparison."

The SAPPHIRE trial is a pivotal study... [but] the small sample size and the study end points preclude major conclusions about the relative roles of endarterectomy and carotid-artery stenting.

In his editorial, Cambria raises several issues about the SAPPHIRE trial. Specifically, he notes that more than 20% of patients in each treatment group were treated for recurrent carotid-artery stenosis, biasing the results in favor of stenting for two reasons: "First, 'redo' endarterectomy is typically associated with higher rates of complications (especially cranial-nerve injury) than is the primary operation, and second, carotid-artery stenting for recurrent disease is inherently less risky when the disease is intimal hyperplasia rather than complex plaque (ie, there is less risk of embolization)," he writes.

He also points out that differences in the primary composite end point at one year are related to the higher incidence of perioperative MI in the endarterectomy group, an end point not used in previous endarterectomy studies. Yadav and colleagues have defended including MI as part of the composite end point because the occurrence of Q-wave or non-Q-wave infarction in the perioperative period increases the risk of future complications and death.

"The SAPPHIRE trial is a pivotal study; its hypothesis that carotid-artery stenting is not inferior to endarterectomy is a valid conclusion," concludes Cambria. "However, the small sample size and the study end points preclude major conclusions about the relative roles of endarterectomy and carotid-artery stenting in the treatment of carotid-artery stenosis."

Commenting on the study and editorial, Dr Deepak Bhatt (Cleveland Clinic, OH) told heartwire that while SAPPHIRE validated carotid stenting as an effective and appropriate tool for symptomatic and asymptomatic patients, the benefits would likely extend further.

SAPPHIRE is a landmark study, and I don't use that term in a cavalier sense.

"SAPPHIRE is a landmark study, and I don't use that term in a cavalier sense," said Bhatt. "I also think the results of SAPPHIRE can probably be extrapolated to the whole universe of patients who might otherwise undergo carotid endarterectomy. Now, that's a controversial statement. Purists will say that the data apply only to the population in which they were obtained, and strictly speaking, that's correct. But it's difficult for me to imagine how the data could qualitatively reverse in low-risk patients. It doesn't make sense."

Bhatt added that he believes the editorial is fair and well balanced, but "conservative" and "cautious." While some, like Cambria, are calling for large-scale trials before major conclusions are made about the relative roles of endarterectomy and carotid stenting, Bhatt said replicating the study will be difficult, as many clinicians already feel stenting is superior to endarterectomy.

The trial was actually stopped prematurely in June 2002 because of slowing enrollment, with increasing resistance on the part of both patients and physicians to randomization.

"Progress is inevitable, and carotid stenting is going to become the reality, the dominant mode for the treatment of carotid stenosis," he said. "There will be some that want to wait until all the data are in, and there will be some that want to jump on board sooner, but the handwriting is on the wall for vascular surgery. Carotid endarterectomy has a very limited lifespan."

An ongoing National Institutes of Health-sponsored trial, the Carotid Revascularization vs Stenting Trial (CREST) is comparing carotid stenting with surgery in lower-risk patients who do meet the criteria for surgery and should help determine whether carotid stenting will ultimately be used in more patients requiring revascularization.