The SAPPHIRE and ARCHeR Updates
A report on the early progress of two trials critical to our understanding of carotid artery stenting.
To view the table related to this article, please refer to the print version of our September issue, page 77.
Physicians in every endovascular specialty anxiously await the continuing results of two major clinical evaluations of the safety and efficacy of carotid artery stenting (CAS)—SAPPHIRE and ARCHeR. These trials are important because they may supply the data necessary to support an FDA decision to approve the procedure in the US. The SAPPHIRE is especially important because it compared CAS to carotid endarterectomy (CEA) in a randomized fashion. Its results will likely legitimize CAS, which has been viewed by some as a dangerous experimental procedure and which many believed could never match the results of CEA, which has withstood the test of time. CAS has even gained notice among the national media, as is evidenced by coverage on the front page of the November 20, 2002 edition of The New York Times, which compared the complication rate for surgery (12.6%) versus that for CAS (5.8%). If this new finding holds up, the article states, CAS may become the preferred procedure for 200,000 Americans who might otherwise choose to undergo surgery.
THE CORDIS/JOHNSON & JOHNSON SAPPHIRE TRIAL
The SAPPHIRE trial is a prospective clinical trial for CAS in high-surgical-risk patients. The 30-day preliminary results were reported at the American Heart Association meeting in Chicago, November 2002, by Jay Yadav, MD, Co-Principal Investigator of the trial.1 A study overview identified 29 investigational sites in the multicenter, randomized trial evaluating CAS in patients who are at high risk for CEA. All patients were evaluated by a team composed of a neurologist, a surgeon, and an interventionist. Randomization to either CEA or CAS required a team consensus; if a surgeon believed that surgery carried prohibitive risk, the patient was entered into a stent registry. Conversely, if the interventionist believed that stenting carried prohibitive risk, the patient was placed into a surgical registry.
Symptomatic patients with &Mac179;50% stenosis determined by ultrasound, and asymptomatic patients with &Mac179;80% stenosis, also determined by ultrasound, were eligible for enrollment, assuming they met the necessary entry criteria. Follow-up duplex and neurologic examinations were scheduled for 30 days, 6 months, 1 year, and annually for 3 years. The primary endpoint was a composite of stroke, death, and myocardial infarction at 30 days, and ipsilateral stroke or death between 31 days and 1 year. The secondary endpoints also included vessel patency (at 48 hours, 6 months, and 1, 2, and 3 years), disabling stroke (at 30 days, 6 months), composite major adverse events (at 6 months, and 1, 2, and 3 years), and safety assessment of the AngioGuard XP (Cordis Endovascular, a Johnson & Johnson company, Miami, FL) embolic distal protection device.
The stent utilized in the SAPPHIRE trial was the self-expanding nitinol PRECISE stent (Cordis Endovascular), available in dimensions of 5 mm to 10 mm in diameter and 20-, 30-, and 40-mm lengths (Figure 1). Also available for use in this trial were 8 mm to 6 mm, 9 mm to 7 mm, and 10 mm to 7 mm tapered self-expanding PRECISE stents. The AngioGuard distal protection device consists of a polyurethane filter over a nitinol basket with a diameter of 6 mm to 8 mm and and a pore size of 100 µm to maintain satisfactory perfusion during the endovascular procedure (Figure 1).2
Assuming the patient met the key inclusion criteria of degree of stenosis, he was also evaluated and had to meet at least one of the high-risk criteria:
• Congestive heart failure (class III/IV) and/or known severe left ventricular dysfunction LVEF <30%
• Open heart surgery within 6 weeks
• Recent myocardial infarction (>24 hours and <4 weeks)
• Unstable angina (CCS class III/IV)
• Coexistent severe coronary artery disease requiring carotid and coronary revascularization
• Severe pulmonary disease (FEV <1.0)
• Contralateral carotid occlusion
• Contralateral laryngeal palsy
• Postradiation treatment
• Previous CEA recurrent stenosis
• High cervical ICA lesions
• CCA lesions below the clavicle
• Severe tandem lesions
• greater than 80 years of age
Seven hundred twenty-three patients were enrolled; 307 were randomized, 409 patients were in the stent registry, and seven patients were in the CEA registry (patients not suitable for CAS).
AngioGuard device delivery placement and retrieval success was reported to be 98.6%. The 30-day, combined death, stroke and/or myocardial infarction rate for the randomized CAS arm was reported to be 5.8% versus 12.6% for the randomized CEA arm (P = .047). Subanalysis showed that in the group of symptomatic patients treated, the death, stroke, and myocardial infarction rate was 4.2% for the randomized stent arm and 15.4% for the randomized CEA arm, whereas it was 6.7% and 11.2%, respectively, for asymptomatic patients. The 30-day death, stroke, and myocardial infarction rate for the stent registry group was reported to be 7.8%.
The SAPPHIRE trial is the first randomized study comparing CAS with embolic protection to carotid endarterectomy. It is also the only high-risk randomized study with stent and surgical registries defined by vascular surgeons. This study provides a surgical complication rate for a large group of high-risk patients who were previously excluded from prior CEA trials. Also, the SAPPHIRE study demonstrates a high technical success rate for CAS using distal protection technology. The remaining primary endpoint (ipsilateral stroke or death between 31 days and 1 year) will be presented at the upcoming 2003 TCT conference. According to a credible source, the benefit of stenting that was apparent at 30 days is expected to hold up at 1 year.
Cordis will soon file their PMA application to the FDA for market clearance. They have also initiated negotiations with the Centers for Medicare & Medicaid Service (CMS) to revise their national ?noncoverage policy? for CAS. FDA approval is expected in the second quarter of 2004, and CMS reimbursement is expected in early 2005. Whether CAS will only be approved and reimbursed strictly for high-risk patients is unknown at this time.
THE GUIDANT ARCHeR TRIAL
The ARCHeR trial is a prospective clinical trial for CAS in high-surgical-risk patients and nonsurgical patients. The 30-day preliminary results were reported at the recent American College of Cardiology meeting in Chicago, March 2003, by Mark Wholey, MD, Co-Principal Investigator of the trial, and at the Society of Interventional Radiology conference in Salt Lake City, March 2003, by Gus Eles, MD.3 A study overview identified 41 investigational sites in the multicenter, single-arm trial evaluating CAS in patients who were at high risk for CEA. All patients were seen by an independent neurologist for assessment prior to enrollment and for continued follow-up. Symptomatic patients with &Mac179;50% stenosis determined by angiography, and asymptomatic patients with &Mac179;80% stenosis, also determined by angiography, were eligible for enrollment assuming they met the necessary entry criteria.
Clinical follow-up examinations are scheduled for 30 days, 6 months, 12 months, 18 months, 24 months, and 30 months. The primary endpoint is a composite of stroke, death, and myocardial infarction at 30 days, and ipsilateral stroke between 31 days and 1 year. Another primary endpoint is the acute success with the ACCUNET Embolic Protection System (Guidant Corporation, Indianapolis, IN). The key secondary endpoints are target lesion revascularization at 6 and 12 months; duplex carotid ultrasound evaluation at 6, 12, and 24 months, and the ACCULINK Carotid Stent System success (Guidant Corporation).
The device evaluated in the ARCHeR trial was the self-expanding, nitinol ACCULINK stent, available in dimensions of 5 mm to 10 mm in diameter, with 20-, 30-, and 40-mm lengths (Figure 2). Also available were 8-mm to 6-mm and 10-mm to 7-mm tapered self-expanding stents. The ACCUNET filter consists of a polyurethane filter over a nitinol basket with a diameter of 4 mm to 8 mm and a pore size of 120 microns to maintain satisfactory perfusion during the endovascular procedure (Figure 2).2
Assuming the patients met the key inclusion criteria for degree of stenosis, they were also evaluated as to the high-risk inclusion criteria. Patients were determined to be high risk by meeting criteria in one of two classification systems (Table 1).
Five hundred thirteen patients were enrolled. Seventy-six of these patients represented a lead-in prior to the registry. Four hundred thirty-seven patients in the registry were enrolled. The demographics in this subset included a history of stroke in 28% and transient ischemic attacks in 24%. The mean age was 69.4 years; 66.6% of the patients were male, and 33.4% were female. Diabetes was present in 39.1% of the patients and 83.9% had hypertension and 68.8% had hyperlipidemia. Other patient data included 32.2% of the patients had restenotic lesions after previous CEA, 28.6% of the patients had ejection fractions of <30% or New York Heart Association classification of III or higher, 27.5% had two or more diseased coronary arteries, and 14.6% had contralateral internal carotid artery occlusion. The remainder was composed of patients with unstable angina, surgically inaccessible lesions, previous radiation therapy, dialysis-dependent renal failure, and contralateral laryngeal nerve damage.
Successful ACCUNET device delivery, placement, and retrieval were reported for 92% of the patients. Debris, either macroscopic or microscopic, was present in the filter baskets in 57% of the patients.
The incidence of 30-day stroke events was minor ipsilateral stroke (3.7%), major ipsilateral stroke (1.4%), and major contralateral stroke (0.2%). Non–stroke-related deaths were 1.6%, and stroke-related death was 0.7%. Myocardial infarction, both Q wave and non-Q wave, accounted for 2.1% of the 30-day events. The overall stroke and death rate was 6.6%, and stroke, death, and myocardial infarction rates were 7.8%. There were 141 patients with restenotic lesions from previous endarterectomy, and in that subset, stroke and death accounted for only 0.7% of patients undergoing CAS. Patients with contralateral ICA occlusions (n = 66) had a stroke, death, and myocardial infarction rate of 7.6% (the combined stroke and death rate was 4.5%). Both of these patient subsets had significantly lower event rates than historical controls. For example, in contralateral ICA occlusions in the NASCET study (North American Symptomatic Carotid Endarterectomy Trial), a 14% periprocedural stroke and death rate was reported. Two or more comorbidities were present in 187 patients; the combined stroke and death rate was only 4.8%, and the combined stroke, death, and myocardial infarction rate was 6.4%.
What was quite significant, however, was that dialysis-dependent renal failure had a stroke, death, and myocardial infarction rate of 28.6%. Only 14 patients were represented in that subset, but it does raise the question in this subset of patients that renal failure may indeed be a predictor for complication.
The ARCHeR trial, representing one of the high-risk trials, demonstrated that CAS with filter protection can be safely performed in high-risk patients in a multicenter trial. The data appear to compare favorably with the historical CEA outcomes in high-risk cohorts. The data are also consistent with the previously presented SAPPHIRE trial results and are additional evidence that CAS is a viable and possibly better alternative to CEA in select high-risk patients. The availability of alternative treatment options may improve the overall outcome of treating carotid stenosis.
Two important controlled clinical trials have been completed and provide data and clinical experience in a specific cohort of patients who can benefit from CAS, namely those with clearly defined increased risk for CEA. Whereas some dispute the definition of “high-risk” from a surgical point of view, very specific definitions were established based on published data. The randomized data seem particularly powerful, and given the difficulty in successfully completing randomized trials in this area, it is likely that it will be some time before we see other randomized data. These data also support what we are seeing in the community, namely acceptance by physicians involved in the medical and surgical care of patients with carotid occlusive disease, who increasingly rely on CAS for treatment of high-risk patients.
Barry Katzen, MD, is the Founder and Medical Director of Miami Cardiac & Vascular Institute, an affiliate of Baptist Health Systems of South Florida, and is a Clinical Professor of Radiology at the University of Miami School of Medicine, Miami, Florida. He receives educational grants from Cordis and Guidant. Dr. Katzen may be reached at email@example.com.
John R. Laird, Jr, MD, is Director of Peripheral Vascular Interventions at the Cardiovascular Research Institute, and is Assistant Clinical Professor of Medicine at Georgetown University Medical Center, Washington, DC. He is also the Co-Director of the Center of Vascular Care at the Washington Hospital Center, Washington, DC. He receives research support from Cordis. Dr. Laird may be reached at (202) 877-5975; John.R.Laird@medstar.net.
Takao Ohki, MD, is Chief of Vascular and Endovascular Surgery at the Montefiore Medical Center, and is Associate Professor of Surgery at the Albert Einstein College of Medicine, New York, New York. He is a consultant for Medtronic. Dr. Ohki may be reached at (718) 920-4707; firstname.lastname@example.org.
1. Yadav J. Stenting and angioplasty with protection in patients at high risk for endarterectomy (The SAPPHIRE Study). AHA Scientific Sessions. November 2002, Chicago, IL.
2. Wholey M, et al. The ARCHeR trial: prospective clinical trial for carotid stenting in high surgical risk patients-preliminary 30-day results. American College of Cardiology annual meeting. March 2003, Chicago, IL.
3. Ohki T, Veith FJ. Carotid artery stenting: utility of cerebral protection devices. J Invas Cardiol. 2001;13:47-55.