At the recent VEITH Symposium in New York, one of the premier vascular meetings in the calendar, there was the usual mixture of debate and controversy. Under discussion was the validity of the recent SAPPHIRE results and whether it is really necessary to use computered tomography (CT) scanning post-EVAR. In addition, the latest technological advances were showcased as well as the latest results from several major studies.
SAPPHIRE not such a gem?
Following the frustration cited by some vascular surgeons at the decision by the Centers for Medicare & Medicaid Services (CMS) in March 2005 to limit reimbursement for carotid stenting to symptomatic patients with severe stenosis of =70%, one of the more captivating debates at VEITH was between Sir Peter Bell and Dr Ken Ouriel. In his presentation, Ouriel supported the view that the two-year SAPPHIRE results were good for enthusiasts, of carotid artery stenting, while Bell maintained that the SAPPHIRE results had limitations that justified the CMS’ decision. The two heavyweights certainly did not disappoint.
The Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy (SAPPHIRE) trial recruited a total of 334 patients, randomized to either stenting or surgery (167 in each group).
Ouriel began by stating that SAPPHIRE was a randomized trial providing level 1 evidence. It showed that after one year, those symptomatic patients who received surgery were more likely to have had a major adverse event (defined as death, stroke or myocardial infarction), than those patients who received a stent (20.0% vs 16.3%, p=0.58). Furthermore, Ouriel argued, after the same time period, asymptomatic patients who received surgery were more likely to have had a major adverse event than those patients who received a stent (20.3% vs 10.5%, p=0.04). After two years, the results showed that the cumulative percentage of patients who had suffered a major adverse event after undergoing surgery increased to 26.4%, compared to 19.6% for stenting.
In terms of one-year stroke rates alone, Ouriel stated that 5.8% of patients who received a carotid endarterectomy suffered a stroke compared to 4.9% of patients who received a stent. Furthermore, at two years, 6.8% of patients who had carotid endarterectomy suffered a stroke, compared to 6.4% of patients who received a stent.
Regarding target lesion revascularization rates, two-year results again favoured stenting with a rate of 1.4%, compared with 6.1% for surgery.
Ouriel said that the results demonstrated that carotid stenting performed at least as well as endarterectomy in higher-risk patients and that the findings held for both symptomatic and asymptomatic subgroups. Therefore, Ouriel concluded, “the SAPPHIRE results provide objective data to justify stenting as an alternative for patients at higher than normal risk for carotid endarterectomy”.
In response, Bell delighted the audience with some wry observations and cynical analyses of the SAPPHIRE results. He argued that examination of the data and methods used to reach the conclusions revealed limitations of the trial. Bell cited several flaws in the study including:
1) inability to detect differences in subgroups;
2) inappropriate extrapolation to clinical practice;
3) failure to set the correct endpoints;
4) failure of equipoise; and
5) biased presentation of results, including failure to report negative results.
Bell stated that the results of the SAPPHIRE trial showed that carotid stenting is equivalent to endarterectomy and avoids all the nasty complications of surgery. Following publication of SAPPHIRE in the New England Journal of Medicine and the approval of carotid stenting by the FDA based on the its results, he commented that there were two key alternative findings: 1) we can no longer trust the FDA; and 2) the New England Journal of Medicine is now in the same academic league as the Wall Street Journal.
Bell said that invasive treatment of any kind to treat carotid stenoses can only be justified if the benefits significantly outweigh the risks compared with non-invasive treatment (ie medical therapy). He posed the question, “Do the results of the SAPPHIRE trial mean that stenting is equivalent to or better than surgery for treating carotid stenosis?” “No not really,” he answered. “This is a great example of how not to do a trial!”
Bell observed that the SAPPHIRE trial was funded by Cordis, a Johnson & Johnson company, who had a vested interest in the outcome of the trial. Not that he was insinuating any bias, merely highlighting that the maker of the devices used in the trial will benefit financially from widespread insertion of the devices (the Precise nitinol self-expanding stent and Angioguard XP Emboli Capture guidewire system). Specifically, he commented, in order for a trial to be perceived as being free from bias, those involved in the trial should not be biased towards either treatment arm and should have no vested interest in the outcome (a condition known as equipoise). However, in the SAPPHIRE trial one of the investigators was the inventor of the protection device and a known supporter of stenting, and was presumably involved in the design of the trial. “This,” said Bell, “is not equipoise.”
He continued, “In randomized trials (level I evidence), which this trial claims to be, randomization should be unbiased with a low false positive or negative rate. In this trial there had to be a consensus before a patient was randomized. What does this mean? Inclusion and exclusion criteria should be established before the trial starts and not be open to moving the goalposts.”
For example, Bell cited the fact that 409 patients were not randomized because the
surgeons concerned felt they were too risky to operate on. “I have thought carefully about my reasons for not operating on such patients,” Bell said, “and can think of only two that are seen from time to time. These are the string sign or a very high lesion, which occurs in very few cases.
“The fact that so many patients were excluded by the surgeons for reasons that have never been explained suggests that these surgeons were not experienced, such exclusions are rare in experienced hands. For the same reason, these surgeons would also be expected to have a higher than average stroke and death rate after surgery. This is confirmed by the fact that more than half did fewer than 30 procedures a year.”
Patients in randomized trials should be similar. Endpoints should be hard and not favor either arm of the trial as the result will depend on the endpoints chosen at the outset. However, in SAPPHIRE 70% of patients were asymptomatic and many patients had restenosis or a hostile neck. Therefore, all of these subgroups have a very different outcome after treatment, “this was essentially a trial of asymptomatic patients,” he commented.
The endpoints of SAPPHIRE included stroke and death, myocardial infarction and biochemical evidence of myocardial infarction. As anesthesia is known to cause myocardial infarction, and as all patients had a general anesthetic, the outcome of the trial was a foregone conclusion, Bell argued. “Local anesthesia was not even mentioned as a possibility in so called high-risk cases”.
Regarding the 30-days endpoints, Bell said that the risk of stroke and death at 30-days with surgery was 6.1% while with stenting it was 5.8% (in mostly asymptomatic patients). For contrast he cited the recent Asymptomatic Carotid Surgery Trial that reported an equivalent figure of 3.1% for surgery. “One again wonders about the surgeons in the SAPPHIRE trial,” Bell commented. “Without any treatment these patients have a stroke and death rate of about 1% at 30 days. Stenting is therefore causing about 4% more needless strokes at 30 days. It is disappointing if a 5.8% stroke and death rate is the best that experts can do in a largely asymptomatic group,” Bell said. “The trial should be consigned to the academic dustbin until the results of much better trials now underway give us some real answers. It is certainly not an indication to widen the use of stenting!”
He concluded, “It is our duty as physicians to protect our patients and not expose them to risks. The new trials now being done will hopefully give us the answer. The SAPPHIRE trial has certainly not done so.”