- Email: [email protected]
Clinical Trials: Past, Present, and Future
Clinical Trials: Past, Present, and Future William A. Gray, MD Carotid stenting has been in evolution for the past 15 years. Initially limited by a lack of dedicated equipment, pivotal trials using both dedicated stent technology and embolic protection filters in patients at high risk for surgical endarterectomy have been largely completed, and results have compared favorably to both direct and historical surgical controls. While this has led to Food and Drug Administration approval of at least six carotid stent systems in the US, European randomized trials in standard surgical risk patients have had mixed results and confused the perception of the place of this technology in the care of patients with carotid stenosis. Current US trials are in progress, one nearing completion, and they will further contribute an understanding as to the place of stent therapy in the standard surgical risk patient, regardless of symptomatic status. Semin Vasc Surg 21:80-87 © 2008 Elsevier Inc. All rights reserved.
S
INCE THE ADVENT of the carotid stent procedure in the United States more than a decade ago, there have been several clinical trials of relevance, and they can generally be divided into three temporal categories: before development of embolic protection and dedicated stent implants (pre1999); after these developments and as part of a Investigational Device Exemption (IDE) seeking US Food and Drug Administration (FDA) approval (⬃1999 to 2005) for patients with high surgical risks; and post⫺market surveillance (PMS) studies initially mandated by the FDA and subsequently extended by the sponsors (⬃2005 to present). Spanning the last two eras and on into the future of carotid stenting are the National Institutes of Health (NIH) Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial and the Abbott Vascular Asymptomatic Carotid Trial (ACT) I trial, both of which address stenting in the standard-surgical risk patient. In addition, three European trials—Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S), and the Stent Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE)—will be included here as well because, for better or worse, they have had a significant impact on the practice of carotid stenting in the United States. Prior to any discussion of carotid intervention trial results, it is important that the metrics used to measure outcomes in
Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY. Address reprint requests to William A. Gray, Cardiovascular Research Foundation, Columbia University, 161 Fort Washington Avenue, 5th Floor, New York, NY 10032. E-mail: [email protected]
80
0895-7967/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semvascsurg.2008.03.007
all of these trials are well understood. Based on the published disparity in the surgical endarterectomy literature between results reported by surgeons and those reported by neurologists, demonstrating a threefold increase in stroke,1 all carotid stent trials incorporated an independent neurologist to evaluate the patient both before and after the procedure, and at 30-day and 1-year assessments. Therefore, outcomes surveillance in carotid stent trials was considerably more sensitive than any self-reported or retrospective reviews of endarterectomy outcomes, and any attempt at comparison between the two therapies should take into account the lack of independent neurologic outcomes assessment in much of the surgical literature, save for the large multicenter studies.
Early Days of Carotid Stenting The first multicenter randomized trial involving carotid stenting to be completed was the CAVATAS trial.2 The trial was initiated in 1992 before the option of stenting was available; stenting was rolled into the trial late in its course and ⬃25% of all patients treated in the interventional arm received stents. Therefore, the trial is largely one of angioplasty outcomes compared with endarterectomy, and without any embolic protection. Nevertheless, results between the two therapies were strikingly similar. In approximately 500 mostly symptomatic patients (⬎90% with symptoms within 6 months of randomization), there were no differences at either 30 days or 3 years between groups in the incidence of death, any stroke, or disabling stroke. Two aspects of the study were especially noteworthy: the 9.9% incidence of stroke and death at 30 days for the endarterectomy arm of the study, which was higher than the 6.5% and 7.0% in similar populations in North American Symptomatic Carotid Endar-
Clinical trials: past, present, and future
81
Table 1 Carotid Wallstent Trial Results Stent (n ⴝ 108)
Surgery (n ⴝ 115)
Event (1 year)
%
n/N
%
n/N
% Difference
P Value
Study-related death or ipsilateral stroke (1° endpoint) Study-related death Ipsilateral stroke Major Minor Undetermined
12 6 7 2 2 2
12/98 6/98 6/92 2/92 2/92 2/92
4 2 3 1 0 2
4/91 2/91 3/90 1/89 0/89 2/90
7.8 3.9 3.2 1.1 2.2 0.0
.067 .28 .49 .00 .49 .00
terectomy Trial (NASCET)3 and the European Carotid Surgery Trialists (ECST)4 studies, respectively, and the durability (lack of stroke or restenosis) of both procedures to 3 years follow-up. Initiated by Schneider in 1996, the first multicenter randomized US study of carotid stenting, the Carotid Wallstent Trial, tested the tracheobronchial Wallstent device without embolic protection in symptomatic patients considered standard risk for endarterectomy. Approximately 200 patients were randomized when the Data Safety Monitoring Board (DSMB) halted the trial in 1999 because it determined that the noninferiority endpoints of the trial would not be achieved at the anticipated enrollment goal of 600 patients. Results of the trial are detailed in Table 1; although 1-year outcomes for stenting and surgery were not statistically different, a strong trend favoring surgery was noted. There were several critiques of this first attempt at carotid stent randomized trial designed and conduct, specifically among them: 1. Lack of a Phase I trial limited the ability to statistically power this pivotal trial because outcomes with carotid stenting using this device were not known outside of single-center reports, as well as to understand the pitfalls of a CAS trial. 2. Endpoint definitions were problematic. 3. Nondedicated equipment was unlikely to match well to a 50-year-old operation. a. Tracheobronchial Wallstent (requiring 8F sheath and with a 0.035 wire lumen mismatched to the 0.018” wires typically used at that time). b. No embolic protection device incorporated. 4. Inadequate operator training. a. A three-case minimum for inexperienced operators in this trial 5. No Principal Investigator or Executive Committee. a. Evolving technique not communicated. b. Site certification not performed according to a trial standard. Many of these and other observations were incorporated into next-generation trial designs making them considerably more robust.
Era of Device Approval Through the efforts of the medical device industry working with physicians providing device and clinical trial feedback, design feedback, dedicated stent implants and embolic protection devices were developed through the late 1990s. After a series of feasibility trials, pivotal trial work was begun in the form of IDE studies intended to achieve US market approval for the various devices. These studies targeted patients at increased surgical risk for an endarterectomy due to either a medical or anatomic reason and where data from previous landmark trials were either lacking owing to their exclusion, or suboptimal surgical outcomes were noted in published registries. While several of these high surgical⫺risk trials are ongoing, seven such trials have been completed, totaling at least 3,000 patients treated in multicenter, neurologically controlled, angiographic core laboratory, and clinical events committee⫺adjudicated studies, and with data from four published (data are available for the others through public presentations at major meetings). These trials are divided into either randomized (eg, Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy [SAPPHIRE]5 or registry (eg, ACCULINK for Revascularization of Carotids in High-Risk Patients [ARCHeR],6 Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients [BEACH],7 Carotid Artery Revascularization Using the Boston Scientific FilterWire EX/EZ™ and the EndoTex™ NexStent™ [CABERNET], Carotid Revascularization with ev3 Arterial Technology Evolution [CREATE],8 Evaluation of the Medtronic AVE SelfExpanding Carotid Stent System with Distal Protection in the Treatment of Carotid Stenosis [MAVeRIC], and A Registry Study to Evaluate the Emboshield/NeuroShield™ Bare Wire Cerebral Protection System and Xact™ Stent in Patients at High Risk for Carotid End arterectomy [SECuRITY]) investigations. All were designed as noninferiority studies, with a direct surgical comparator in the SAPPHIRE study, and objective performance criteria (OPC) agreed to by the FDA for registry studies. OPCs in the registry studies were surrogates for a randomized arm because randomization was becoming increasingly difficult at that time. OPCs were derived specifically for each registry study, were based on outcomes for endarterectomy derived from the literature (where none existed, outcomes for the medical therapy arm was used), and
W.A. Gray
82 Table 2 Inclusion Criteria for the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Trial General criteria Age older than 18 years Unilateral or bilateral atherosclerotic of restenotic lesions in the native carotid arteries Symptoms plus a 50% ipsilateral carotid stenosis No symptoms plus an 80% carotid stenosis Criteria for high risk (at least one factor required) Clinically significant cardiac disease (CHF, abnormal stress test, or need for open heart surgery) Severe pulmonary disease Contralateral carotid occlusion Contralateral cranial nerve palsy Previous radical neck surgery or radiation therapy to the neck Recurrent stenosis after endarterectomy Age older than 80 years Exclusion criteria Ischemic stroke within 48 hours Presence of intramural thrombus Total occlusion of target vessel Vascular disease precluding use of catheter-based techniques Intracranial aneurysm >9 mm in diameter Need for more than two stents History of bleeding disorder Percutaneous or surgical intervention planned within the next 30 days Life expectancy <1 year Ostial lesion of the common carotid artery or brachiocephalic artery
ority of these primary outcomes, rates of target vessel revascularization (a repeat percutaneous or open surgical intervention performed at the site of the initial intervention) (0.6% v 4.3%; P ⫽ .04) and cranial nerve palsy (0% v 4.9%; P ⫽ .003) favored stenting. It was on the basis of these data that in April 2004, an FDA panel advisory voted to recommend approval of the devices used in this trial. After the SAPPHIRE randomized trial, a series of (ongoing) registries were undertaken and successfully completed or are in the process of being completed, gaining FDA approval for the respective devices (Table 3). For the purposes of this discussion, these registries will be discussed as an amalgam because they had similar eligibility, definitions, and endpoints, although they are not directly comparable to each other because of some differences in these qualities. Like SAPPHIRE, all registries were multicenter and clinical events committee⫺adjudicated and had independent neurological audit, independent angiographic, and ultrasound core labs; eligibility requirements were similar to those outlined for SAPPHIRE. The 1-year primary endpoints were also similar to SAPPHIRE, although the majority of these registries did not count neurologic or other death past 30 days. In general, device success was very good, with more than 95% of filters and ⬃99% of stents successfully placed. Figure 2 is a summary of 30-day outcomes in these registries and is contrasted to 30-day endarterectomy outcomes in SAPPHIRE, which serves as a contemporary comparison. Other findings from these pivotal investigations of note include the following:
Abbreviation: CHF, congestive heart failure.
●
prorated the outcomes of high surgical⫺risk features specific to each registry and their particular enrollment percentage. In most cases, the calculated OPCs were similar to the actual surgical comparator (using a similar definition) in SAPPHIRE of 12.6% major adverse outcomes at 12 months, thus validating their use as a rational comparator. The SAPPHIRE study enrolled 747 high surgical⫺risk patients between 2000 and 2002, 334 into the randomized arm and 413 into either a stent or surgical registry based on review of the multidisciplinary panel (surgeon, neurologist, interventionalist) at each participating institution; the randomized data have been published but, to date, the registry results have not been published and will not be discussed here. The Precise stent and Angioguard filter emboli protection systems were used in the interventional arms of this study. Eligibility criteria for the study are shown in Table 2. There were no demographic or baseline medical history differences between the groups in the randomized arms, with ⬃28% of the patients being symptomatic and ⬃20% older than 80 years of age. The primary endpoint using the KaplanMeier method (death, stroke, myocardial infarction at 30 days plus ipsilateral stroke or neurologic death 31 days to 1 year) was 12.2% and 20.1% (P ⫽ .05) for stenting and surgery, respectively (Fig 1). In addition to achieving noninferi-
●
● ●
The impact of periprocedural minor strokes was negligible at 1 year, with the patient registering an NIH Stroke Score of 0 or 1 in all cases (ARCHeR). Filter deployment time of more than 20 minutes was associated with worse outcomes in a multivariable analysis (CREATE). Target lesion revascularization appeared to be low, averaging ⬃1%/year in most studies. Unpublished data from a prospective analysis of costs in the SAPPHIRE trial demonstrated no differences in cost between stenting and surgery both in-hospital and at 1
Figure 1 Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) Kaplan-Meier analysis of primary 1-year endpoint.
Clinical trials: past, present, and future
83
Table 3 US Trials in Carotid Stenting Name of Stent
Manufacturer
Precise Acculink EXACT WallStent NexStent Exponent Protégé Vivexx Fibernet (filter)ⴙany approved stent Gore NPS (flow-reversal)ⴙany approved stent
Cordis Endovascular/J&J Guidant/Abbott Vascular Abbott Vascular Boston Scientific Endotex/Boston Scientific Medtronic ev3 BARD Lumen Medical WL Gore
Trial Name (No. of Patients)
Trial/FDA Status
SAPPHIRE (716)* ARCHeR (581)* SECURITY (305) BEACH (480)* CABERNET (454) MAVErIC II (399) CREATE (419)* VIVA EPIC EMPIRE
Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/pending Ongoing Ongoing
*Published data available.
year, with a highly cost-effective $/quality adjusted life-year. Important long-term follow-up from several of these pivotal trials has yielded important efficacy and durability data for carotid stenting. In the SAPPHIRE study, incidence of stroke after the first 30 days following the procedure (ie, exclusive of periprocedural stroke) and to 3 years was indistinguishable between endarterectomy and stenting, providing confirmation of the stroke-prevention efficacy of stenting. In addition, the rate of target lesion revascularization following stenting was very low, and at 3 years was less than half that associated with endarterectomy. The ARCHeR registries confirmed both the low rates of stroke and repeat intervention, each of which averaged ⬃1% per year. Finally, rates of survival at 3 years in these studies appears to be similar to prior standard-risk endarterectomy studies; in spite of the high surgical⫺risk nature of these patients, their mortality is not excessive, as some have suggested, and are therefore likely to benefit from the procedure. Conclusions from these pivotal trials regarding carotid stenting were that the volume of data were robust and remarkably consistent across trials, devices, operators, and sites; in all cases
stent outcomes were noninferior to endarterectomy in either direct comparison or a weighted historical control; and that costs associated with these results were similar between therapies. Moreover, for stenting both the effectiveness of stroke prevention and durability of vessel patency were demonstrated relative to surgical revascularization. Confirming these pivotal high surgical⫺risk trial conclusions was the all-comer Carotid Revascularization Using Endarterectomy or Stenting Systems (CARESS) study.9 This was a nonrandomized equivalence cohort investigation between 2001 and 2002, which allowed local practice to dictate the choice of therapy with enrollment in a 2:1 ratio (surgery to endovascular) in all patient subsets (ie, not restricted to high surgical risk). Patients in the endovascular arm were treated with the Percusurge Guardwire and the Carotid Wallstent. The primary endpoint in the 397 patients was 1-year death and stroke rate. In spite of its nonrandomized design, the groups differed only in more frequent prior endarterectomy and stenting in the stenting group. At 1 year, there was a trend toward fewer strokes in the stent group (5.5% v 9.8%; P ⫽ .13), but overall no differences between the two treatment groups (13.6% v 10.0%; P ⫽ .30), including in a mea-
Figure 2 Summary of 30-day carotid stent outcomes in US high surgical⫺risk studies.
84 sure of quality of life (Multidimensional Index of Life Quality) although this data set was significantly incomplete. A larger Phase II CARESS trial has been planned but not yet initiated. Two randomized European studies published in 2006 have added to the data available for consideration, but not to the clarity of the place of carotid stenting vis-à-vis endarterectomy. The SPACE trial was a randomized trial in symptomatic moderate-risk surgical patients with carotid lesions ⬎50% (according to the NASCET criteria) conducted in Germany, and was sponsored by several institutions and companies. Three carotid stent systems and five embolic protection systems were approved for use in this trial based on their Communite European (CE) mark availability, and the primary endpoint of the study was ipsilateral stroke and death from any cause at 30 days. The statistical design of the trial called for a 2.5% noninferiority margin assuming a true event rate of 5% in each group and, based on a 5% alpha and 80% power, 950 patients were needed per treatment group. Prespecified interval analyses were performed, as well as subgroup analyses according to age and gender at the completion of the trial. Important to note in this trial, only 27% of patients in the stent arm had embolic protection devices used. The SPACE steering committee stopped the study after enrolling approximately 1,200 patients between 2001 and 2006, based on a second interim analysis suggesting at the observed event rate and actual difference in the therapies that more than 2,500 patients would be required to demonstrate noninferiority, for which the required funding was lacking. Nevertheless, results between the two groups were similar, with a 30-day primary endpoint of 6.34% versus 6.84% (P ⫽ .09). Recently, prespecified analysis demonstrated a significant differential in outcomes according to age for stenting, but not for surgery, which maintained a roughly 6.5% ageindependent event rate. A regression tree analysis gave a separation of outcomes for stenting at 68 years, ie, 2.7% 30-day events under the age of 68 years and 10.8% when older. This translated into an advantage for stenting over surgery in the younger age group.10 In summary, SPACE appears to show near equivalence for the overall cohort of ⬃1,200 symptomatic patients, in spite of a lack of embolic protection in a significant majority of subjects. Failure to achieve noninferiority was the result of unanticipated increases in the total number of patients required and a lack of commensurate funding, but not due to safety or futility concerns. Differential outcomes by age suggest that future trial results should be analyzed accordingly. The Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial11 was conducted in France between 2000 and 2005 and was sponsored by the French government. The trial inclusion was very similar to SPACE. Recently symptomatic patients of moderate surgical risk and carotid stenosis ⬎60% (NASCET criteria) were randomized 1:1 between stenting and surgery, with a 30-day primary endpoint of any stroke or death. In a similar time period, however, EVA-3S enrolled less than half the number of patients in SPACE. The study was stopped after
W.A. Gray 527 patients were randomized on the basis of safety and futility. The primary endpoint was seen in 9.6% of stent and 3.9% of endarterectomy patients (P ⫽ .01). A close look at the trial conduct, however, suggests significant deficiencies in training and low-volume stent operators, which resulted in heretofore unheard of rates of emergency surgery (5% resulting in two strokes, whereas few if any of the ⬎3,000 US pivotal trial patients went to emergency surgery). There was no centralized certification body to assess the preparedness of operators: surgeons had to have performed 25 endarterectomies in the year before enrollment, but a stent operator could have as few as five lifetime procedures to be considered qualified, but no oversight as to use of protection systems or outcomes in those procedures was undertaken. A first-time stenter was permitted to randomize patients under the tutelage of such a qualified operator and, of the sites involved in EVA-3S, two-thirds were under such tutelage at the start of their randomized participation. In addition, the late entry of embolic protection devices, which were mandated after four to five excess strokes in the stent arm during a protectionoptional phase, also may have contributed to excess strokes in the stent group. Nonstandard practices, such as significant use of anesthesia in ⬃30% of patients (estimated ⬍5% in the United States) and lack of predilation before stenting also had unclear effects on outcomes. In summary, the disparate results of these two trials (EVA-3S and SPACE) and glitches in their design and conduct leave the question as to the place of stenting in the management of symptomatic patients at reasonable risk for surgery unanswered. It may very well be that these results are reflective of the true results of stenting, but conclusions in this regard would be difficult to reach based on SPACE and EVA-3S alone. Nevertheless, these highly publicized, albeit flawed, trials have had a real effect on stenting in the United States, based on their publication in the Lancet and the New England Journal of Medicine, and new data will likely be required to change the perception of the therapy.
Data Since Device Approval PMS study data since device approval have been both remarkably plentiful as well as valuable. As a condition of all new device approvals, the FDA stipulates a PMS program be established to identify any rare or unanticipated device-related events (frequency ⬍1%). In case of carotid stenting, the ability to demonstrate the transfer of the technology and technique from the clinical trial setting to the “real-world,” and hence the adequacy of training programs proposed by manufacturers and approved by the FDA was also an important goal of the PMS registries. Important to any discussion of these data is an understanding of the conduct of these studies. In the Carotid Artery Stenting With Emboli Protection Surveillance Post-Marketing Study (CASES-PMS),12 Carotid RX ACCULINK®/RX ACCUNET™ Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE),13,14 Emboshield® and Xact™ Post Approval Carotid Stent Trial (EXACT), and CAPTURE 2 studies, data were collected prospectively, all patients underwent independent neurologic
Clinical trials: past, present, and future
85
Figure 3 Temporal Improvement in CAS Outcomes Since Initial FDA Device Approval in 2004.
evaluation before and after the procedure and again at 30 days, and results were then adjudicated by an independent Clinical Events Committee. These registries have been extended beyond the originally mandated 1,500 patients per manufacturer, and now have data on well over 10,000 patient outcomes. Accordingly, these registries represent the largest multicenter, prospective, neurologically controlled, and adjudicated data sets carotid revascularization therapies ever assembled. Published results of both CASES and CAPTURE registries confirmed that there were no unanticipated device-related events, and that the transfer of the technology to the nontrial larger-scale environment was successful, thereby validating the training programs established by the device manufacturers. Not only were the outcomes of these postapproval studies initially better than even the predicate pivotal trials (SAPPHIRE and ARCHeR), but in the case of the Abbott Vascular data sets, there has been a continuous temporal improvement in the results during the 3 years since broad application postapproval (Fig 3, unpublished data). This is especially relevant because after the landmark NASCET and Asymptomatic Carotid Atherosclerosis Study (ACAS) trials in endarterectomy, 30-day mortality measured in more than 100,000 patients was nearly threefold greater when the surgery was performed outside the trial setting, even in trial hospitals.15 In addition to achieving the stated goals, the PMS registries have provided a wealth of information about the procedure not otherwise available from the much smaller pivotal device-approval trials because they were powered for endpoints typically requiring only 300 to 500 patients, which did not allow any significant subset analysis. Some of the important observations from these registries include: 1. Predictors of adverse outcomes in carotid stenting include:
a. Advanced age (older than 80 years); although this finding is in keeping with most other surgical and interventional procedures, the most recent unpublished data suggest the differential in outcomes in stenting as a function of age is narrowing.12,13 b. Symptomatic patients; similar to endarterectomy symptomatic patients, appear to have not only the greatest benefit from the procedure but also the greatest risk. Different from endarterectomy, patients receiving carotid stenting within the first 2 weeks after symptoms appear to have a roughly twofold increase in outcomes compared to those stented after this initial period.13 This may speak to the temperament of the symptomatic plaque after presumed rupture caused the original symptoms. c. Use of either multiple stents or balloon predilation prior to placement of the embolic protection device. These might be markers of operator inexperience or lesion complexity, or both.13 2. Approximately 20% of all strokes occurring in carotid stenting (an absolute rate of ⬃1%) occur in a nonipsilateral vascular territory; this remained true regardless of the age of the patient, the symptomatic status of the patient, or the experience of the operator.14 It suggests an access-related cause, creating an opportunity to improve outcomes with either better technique or equipment. 3. Approximately one-third of all strokes in carotid stenting are observed more than 24 hours after the procedure. Although the explanations for this finding range from late embolic events to delayed clinical onset of symptoms, they remain speculative. Lastly, the PMS registries for CAPTURE 2 and EXACT, representing the most contemporary data available, demonstrate the achievement of the 3% goals for asymptomatic
W.A. Gray
86 populations outlined by the American Heart Association in their 1998 Guidelines for Endarterectomy. This same goal has never been demonstrated in the high surgical⫺risk population with endarterectomy in a prospective, multicenter, adjudicated survey.
Future Trials The place of carotid stenting in the high surgical⫺risk patient appears to be solidifying, as more data emerge, but the question as to the application of this procedure in the much larger population of standard-risk patients remains unanswered. Two important US trials are currently underway that will add to the increasing understanding of carotid stenting in this population. The CREST trial is a cosponsored trial between the NIH/ National Heart, Lung and Blood Institute and Abbott Vascular, and is randomizing patients with both symptomatic and asymptomatic carotid stenosis who are good surgical candidates for either stenting or endarterectomy in a 1:1 ratio. Started in the late 1990s, with the first randomized patient in December 2000, CREST is now enrolling in more than 110 sites in the United States and Canada, and is approximately 200 patients away from completing its 2,500 patient enrollment; it is projected to be completed in mid-2008. The primary endpoint is 30-day death, stroke, and myocardial infarction plus ipsilateral stroke to 1 year; the trial also acts as an IDE for the devices being used (ACCULINK stent and ACCUNET filter), assuming noninferiority is achieved. The trial was designed well before many of the observations listed previously from the pivotal and PMS studies better characterized carotid stenting, so there may be analyses that would otherwise be prespecified (such as time from symptom to procedure) that will not be included in the initial analysis. Nevertheless, data from this large trial will significantly add to our knowledge base on the relative merits of these two types of carotid revascularization. ACT I is an Abbott Vascular⫺sponsored study randomizing standard-surgical risk asymptomatic patients only to either stenting with the EXACT stent and the Emboshield filter or endarterectomy in a 3:1 ratio. The trial has an endpoint of 30-day death, stroke, and myocardial infarction plus ipsilateral stroke to 1 year. Currently, there are approximately 500 patients entered in this trial, which began in 2005, and anticipated enrollment is approximately 1,800 patients. The Transatlantic Asymptomatic Carotid Intervention Trial (TACIT) study has been in development for several years and although initially rejected for NIH funding, contains an optimal/modern medical therapy arm in addition to revascularization arms in order to address the question raised by many stroke neurologists who point out that none of the trials of surgery or stenting have adequately treated their noninterventional arm with targeted medical therapy, although there is a lack of data for stroke prevention with these therapies in patients with established severe carotid disease. TACIT would hope to answer this concern, and is being formulated as a trans-Atlantic endeavor. ACST 2 (asymptomatic patients) and CAVATAS 2 (symp-
tomatic patients) are both European efforts underway as follow-up to the original studies, this time with express purpose of assessing carotid stenting rather than medication and angioplasty, respectively, compared to surgery.
Summary Carotid stent trial data developed to date as a result of these and other trials eclipse that available in endarterectomy in terms of the prospective, multicenter, and independent assessment of the technology, and compares well in the high surgical⫺risk population. However, because such a population was never clearly defined until carotid stenting came along, carotid stenting remains controversial in this group of patients by those who either do not believe such a population exists in spite of data to the contrary, or does not benefit from any revascularization, surgical or stenting. It likely will remain a procedure with limited patient access until investigation definitively proves its value as compared to endarterectomy in the standard-risk population. Several studies currently underway will hopefully make the technology more available to a broader base of patients who generally prefer nonsurgical methods, assuming equal safety and efficacy.
References 1. Rothwell PM, Slattery J, Warlow CP: A systematic review of the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis. Stroke 27:260-265, 1996 2. CAVATAS Investigators: Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 357:1729-1737, 2001 3. Barnett HJM, Taylor DW, Eliaszaw M, et al: Benefit of carotid endarterectomy in patients with symptomatic carotid stenosis. N Engl J Med 339:1415-1425, 1998 4. The European Carotid Surgery Trialists’ Collaborative Group: Endarterectomy for moderate symptomatic carotid stenosis: interim results from the MRC European Carotid Surgery Trial. Lancet 347:1591-1593, 1996 5. Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351:14931501, 2004 6. Gray WA, Hopkins LN, Yadav S, et al: Protected carotid stenting in high-surgical-risk patients: the ARCHeR results. J Vasc Surg 44:258269, 2006 7. Iyer SS, White CJ, Hopkins LN, et al: Carotid artery revascularization in high-surgical-risk patients using the carotid Wallstent and FilterWire EX/EZ. J Am Coll Cardiol 51:427-434, 2008 8. Safian RD, Bresnahan JF, Jaff MR, et al: Protected carotid stenting in high-risk patients with severe carotid artery stenosis. J Am Coll Cardiol 47:2384-2389, 2006 9. CARESS Steering Committee: Carotid revascularization using endarterectomy or stenting systems (CARESS): phase I clinical trial. J Endovasc Ther 10:1021-1030, 2003 10. Stingele R, Berger J, Alfke K, et al: Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent-protected angioplasty: a subanalysis of the SPACE study. Lancet Neurol 7:216-222, 2008 11. Mas JL, Chatellier G, Beyssen B, et al: EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 19:355:1660-1671, 2006 12. Katzen BT, Criado FJ, Ramee SR, et al: Carotid artery stenting with
Clinical trials: past, present, and future emboli protection surveillance study: thirty-day results of the CASES-PMS study. Catheter Cardiovasc Interv 70:316-723, 2007 13. Gray WA, Yadav JS, Verta P, et al: The CAPTURE registry: predictors of outcomes in carotid artery stenting with embolic protection for high surgical risk patients in the early post-approval setting. Catheter Cardiovasc Interv 70:1025-1033, 2007 14. Fairman R, Gray WA, Scicli AP, et al: The CAPTURE registry: analysis
87 of strokes resulting from carotid artery stenting in the post approval setting: timing, location, severity, and type. Ann Surg 246:551-556; discussion 556-558, 2007 15. Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES: Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA 279: 1278-1281, 1998
S
INCE THE ADVENT of the carotid stent procedure in the United States more than a decade ago, there have been several clinical trials of relevance, and they can generally be divided into three temporal categories: before development of embolic protection and dedicated stent implants (pre1999); after these developments and as part of a Investigational Device Exemption (IDE) seeking US Food and Drug Administration (FDA) approval (⬃1999 to 2005) for patients with high surgical risks; and post⫺market surveillance (PMS) studies initially mandated by the FDA and subsequently extended by the sponsors (⬃2005 to present). Spanning the last two eras and on into the future of carotid stenting are the National Institutes of Health (NIH) Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial and the Abbott Vascular Asymptomatic Carotid Trial (ACT) I trial, both of which address stenting in the standard-surgical risk patient. In addition, three European trials—Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S), and the Stent Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE)—will be included here as well because, for better or worse, they have had a significant impact on the practice of carotid stenting in the United States. Prior to any discussion of carotid intervention trial results, it is important that the metrics used to measure outcomes in
Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY. Address reprint requests to William A. Gray, Cardiovascular Research Foundation, Columbia University, 161 Fort Washington Avenue, 5th Floor, New York, NY 10032. E-mail: [email protected]
80
0895-7967/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semvascsurg.2008.03.007
all of these trials are well understood. Based on the published disparity in the surgical endarterectomy literature between results reported by surgeons and those reported by neurologists, demonstrating a threefold increase in stroke,1 all carotid stent trials incorporated an independent neurologist to evaluate the patient both before and after the procedure, and at 30-day and 1-year assessments. Therefore, outcomes surveillance in carotid stent trials was considerably more sensitive than any self-reported or retrospective reviews of endarterectomy outcomes, and any attempt at comparison between the two therapies should take into account the lack of independent neurologic outcomes assessment in much of the surgical literature, save for the large multicenter studies.
Early Days of Carotid Stenting The first multicenter randomized trial involving carotid stenting to be completed was the CAVATAS trial.2 The trial was initiated in 1992 before the option of stenting was available; stenting was rolled into the trial late in its course and ⬃25% of all patients treated in the interventional arm received stents. Therefore, the trial is largely one of angioplasty outcomes compared with endarterectomy, and without any embolic protection. Nevertheless, results between the two therapies were strikingly similar. In approximately 500 mostly symptomatic patients (⬎90% with symptoms within 6 months of randomization), there were no differences at either 30 days or 3 years between groups in the incidence of death, any stroke, or disabling stroke. Two aspects of the study were especially noteworthy: the 9.9% incidence of stroke and death at 30 days for the endarterectomy arm of the study, which was higher than the 6.5% and 7.0% in similar populations in North American Symptomatic Carotid Endar-
Clinical trials: past, present, and future
81
Table 1 Carotid Wallstent Trial Results Stent (n ⴝ 108)
Surgery (n ⴝ 115)
Event (1 year)
%
n/N
%
n/N
% Difference
P Value
Study-related death or ipsilateral stroke (1° endpoint) Study-related death Ipsilateral stroke Major Minor Undetermined
12 6 7 2 2 2
12/98 6/98 6/92 2/92 2/92 2/92
4 2 3 1 0 2
4/91 2/91 3/90 1/89 0/89 2/90
7.8 3.9 3.2 1.1 2.2 0.0
.067 .28 .49 .00 .49 .00
terectomy Trial (NASCET)3 and the European Carotid Surgery Trialists (ECST)4 studies, respectively, and the durability (lack of stroke or restenosis) of both procedures to 3 years follow-up. Initiated by Schneider in 1996, the first multicenter randomized US study of carotid stenting, the Carotid Wallstent Trial, tested the tracheobronchial Wallstent device without embolic protection in symptomatic patients considered standard risk for endarterectomy. Approximately 200 patients were randomized when the Data Safety Monitoring Board (DSMB) halted the trial in 1999 because it determined that the noninferiority endpoints of the trial would not be achieved at the anticipated enrollment goal of 600 patients. Results of the trial are detailed in Table 1; although 1-year outcomes for stenting and surgery were not statistically different, a strong trend favoring surgery was noted. There were several critiques of this first attempt at carotid stent randomized trial designed and conduct, specifically among them: 1. Lack of a Phase I trial limited the ability to statistically power this pivotal trial because outcomes with carotid stenting using this device were not known outside of single-center reports, as well as to understand the pitfalls of a CAS trial. 2. Endpoint definitions were problematic. 3. Nondedicated equipment was unlikely to match well to a 50-year-old operation. a. Tracheobronchial Wallstent (requiring 8F sheath and with a 0.035 wire lumen mismatched to the 0.018” wires typically used at that time). b. No embolic protection device incorporated. 4. Inadequate operator training. a. A three-case minimum for inexperienced operators in this trial 5. No Principal Investigator or Executive Committee. a. Evolving technique not communicated. b. Site certification not performed according to a trial standard. Many of these and other observations were incorporated into next-generation trial designs making them considerably more robust.
Era of Device Approval Through the efforts of the medical device industry working with physicians providing device and clinical trial feedback, design feedback, dedicated stent implants and embolic protection devices were developed through the late 1990s. After a series of feasibility trials, pivotal trial work was begun in the form of IDE studies intended to achieve US market approval for the various devices. These studies targeted patients at increased surgical risk for an endarterectomy due to either a medical or anatomic reason and where data from previous landmark trials were either lacking owing to their exclusion, or suboptimal surgical outcomes were noted in published registries. While several of these high surgical⫺risk trials are ongoing, seven such trials have been completed, totaling at least 3,000 patients treated in multicenter, neurologically controlled, angiographic core laboratory, and clinical events committee⫺adjudicated studies, and with data from four published (data are available for the others through public presentations at major meetings). These trials are divided into either randomized (eg, Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy [SAPPHIRE]5 or registry (eg, ACCULINK for Revascularization of Carotids in High-Risk Patients [ARCHeR],6 Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients [BEACH],7 Carotid Artery Revascularization Using the Boston Scientific FilterWire EX/EZ™ and the EndoTex™ NexStent™ [CABERNET], Carotid Revascularization with ev3 Arterial Technology Evolution [CREATE],8 Evaluation of the Medtronic AVE SelfExpanding Carotid Stent System with Distal Protection in the Treatment of Carotid Stenosis [MAVeRIC], and A Registry Study to Evaluate the Emboshield/NeuroShield™ Bare Wire Cerebral Protection System and Xact™ Stent in Patients at High Risk for Carotid End arterectomy [SECuRITY]) investigations. All were designed as noninferiority studies, with a direct surgical comparator in the SAPPHIRE study, and objective performance criteria (OPC) agreed to by the FDA for registry studies. OPCs in the registry studies were surrogates for a randomized arm because randomization was becoming increasingly difficult at that time. OPCs were derived specifically for each registry study, were based on outcomes for endarterectomy derived from the literature (where none existed, outcomes for the medical therapy arm was used), and
W.A. Gray
82 Table 2 Inclusion Criteria for the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Trial General criteria Age older than 18 years Unilateral or bilateral atherosclerotic of restenotic lesions in the native carotid arteries Symptoms plus a 50% ipsilateral carotid stenosis No symptoms plus an 80% carotid stenosis Criteria for high risk (at least one factor required) Clinically significant cardiac disease (CHF, abnormal stress test, or need for open heart surgery) Severe pulmonary disease Contralateral carotid occlusion Contralateral cranial nerve palsy Previous radical neck surgery or radiation therapy to the neck Recurrent stenosis after endarterectomy Age older than 80 years Exclusion criteria Ischemic stroke within 48 hours Presence of intramural thrombus Total occlusion of target vessel Vascular disease precluding use of catheter-based techniques Intracranial aneurysm >9 mm in diameter Need for more than two stents History of bleeding disorder Percutaneous or surgical intervention planned within the next 30 days Life expectancy <1 year Ostial lesion of the common carotid artery or brachiocephalic artery
ority of these primary outcomes, rates of target vessel revascularization (a repeat percutaneous or open surgical intervention performed at the site of the initial intervention) (0.6% v 4.3%; P ⫽ .04) and cranial nerve palsy (0% v 4.9%; P ⫽ .003) favored stenting. It was on the basis of these data that in April 2004, an FDA panel advisory voted to recommend approval of the devices used in this trial. After the SAPPHIRE randomized trial, a series of (ongoing) registries were undertaken and successfully completed or are in the process of being completed, gaining FDA approval for the respective devices (Table 3). For the purposes of this discussion, these registries will be discussed as an amalgam because they had similar eligibility, definitions, and endpoints, although they are not directly comparable to each other because of some differences in these qualities. Like SAPPHIRE, all registries were multicenter and clinical events committee⫺adjudicated and had independent neurological audit, independent angiographic, and ultrasound core labs; eligibility requirements were similar to those outlined for SAPPHIRE. The 1-year primary endpoints were also similar to SAPPHIRE, although the majority of these registries did not count neurologic or other death past 30 days. In general, device success was very good, with more than 95% of filters and ⬃99% of stents successfully placed. Figure 2 is a summary of 30-day outcomes in these registries and is contrasted to 30-day endarterectomy outcomes in SAPPHIRE, which serves as a contemporary comparison. Other findings from these pivotal investigations of note include the following:
Abbreviation: CHF, congestive heart failure.
●
prorated the outcomes of high surgical⫺risk features specific to each registry and their particular enrollment percentage. In most cases, the calculated OPCs were similar to the actual surgical comparator (using a similar definition) in SAPPHIRE of 12.6% major adverse outcomes at 12 months, thus validating their use as a rational comparator. The SAPPHIRE study enrolled 747 high surgical⫺risk patients between 2000 and 2002, 334 into the randomized arm and 413 into either a stent or surgical registry based on review of the multidisciplinary panel (surgeon, neurologist, interventionalist) at each participating institution; the randomized data have been published but, to date, the registry results have not been published and will not be discussed here. The Precise stent and Angioguard filter emboli protection systems were used in the interventional arms of this study. Eligibility criteria for the study are shown in Table 2. There were no demographic or baseline medical history differences between the groups in the randomized arms, with ⬃28% of the patients being symptomatic and ⬃20% older than 80 years of age. The primary endpoint using the KaplanMeier method (death, stroke, myocardial infarction at 30 days plus ipsilateral stroke or neurologic death 31 days to 1 year) was 12.2% and 20.1% (P ⫽ .05) for stenting and surgery, respectively (Fig 1). In addition to achieving noninferi-
●
● ●
The impact of periprocedural minor strokes was negligible at 1 year, with the patient registering an NIH Stroke Score of 0 or 1 in all cases (ARCHeR). Filter deployment time of more than 20 minutes was associated with worse outcomes in a multivariable analysis (CREATE). Target lesion revascularization appeared to be low, averaging ⬃1%/year in most studies. Unpublished data from a prospective analysis of costs in the SAPPHIRE trial demonstrated no differences in cost between stenting and surgery both in-hospital and at 1
Figure 1 Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) Kaplan-Meier analysis of primary 1-year endpoint.
Clinical trials: past, present, and future
83
Table 3 US Trials in Carotid Stenting Name of Stent
Manufacturer
Precise Acculink EXACT WallStent NexStent Exponent Protégé Vivexx Fibernet (filter)ⴙany approved stent Gore NPS (flow-reversal)ⴙany approved stent
Cordis Endovascular/J&J Guidant/Abbott Vascular Abbott Vascular Boston Scientific Endotex/Boston Scientific Medtronic ev3 BARD Lumen Medical WL Gore
Trial Name (No. of Patients)
Trial/FDA Status
SAPPHIRE (716)* ARCHeR (581)* SECURITY (305) BEACH (480)* CABERNET (454) MAVErIC II (399) CREATE (419)* VIVA EPIC EMPIRE
Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/approved Completed/pending Ongoing Ongoing
*Published data available.
year, with a highly cost-effective $/quality adjusted life-year. Important long-term follow-up from several of these pivotal trials has yielded important efficacy and durability data for carotid stenting. In the SAPPHIRE study, incidence of stroke after the first 30 days following the procedure (ie, exclusive of periprocedural stroke) and to 3 years was indistinguishable between endarterectomy and stenting, providing confirmation of the stroke-prevention efficacy of stenting. In addition, the rate of target lesion revascularization following stenting was very low, and at 3 years was less than half that associated with endarterectomy. The ARCHeR registries confirmed both the low rates of stroke and repeat intervention, each of which averaged ⬃1% per year. Finally, rates of survival at 3 years in these studies appears to be similar to prior standard-risk endarterectomy studies; in spite of the high surgical⫺risk nature of these patients, their mortality is not excessive, as some have suggested, and are therefore likely to benefit from the procedure. Conclusions from these pivotal trials regarding carotid stenting were that the volume of data were robust and remarkably consistent across trials, devices, operators, and sites; in all cases
stent outcomes were noninferior to endarterectomy in either direct comparison or a weighted historical control; and that costs associated with these results were similar between therapies. Moreover, for stenting both the effectiveness of stroke prevention and durability of vessel patency were demonstrated relative to surgical revascularization. Confirming these pivotal high surgical⫺risk trial conclusions was the all-comer Carotid Revascularization Using Endarterectomy or Stenting Systems (CARESS) study.9 This was a nonrandomized equivalence cohort investigation between 2001 and 2002, which allowed local practice to dictate the choice of therapy with enrollment in a 2:1 ratio (surgery to endovascular) in all patient subsets (ie, not restricted to high surgical risk). Patients in the endovascular arm were treated with the Percusurge Guardwire and the Carotid Wallstent. The primary endpoint in the 397 patients was 1-year death and stroke rate. In spite of its nonrandomized design, the groups differed only in more frequent prior endarterectomy and stenting in the stenting group. At 1 year, there was a trend toward fewer strokes in the stent group (5.5% v 9.8%; P ⫽ .13), but overall no differences between the two treatment groups (13.6% v 10.0%; P ⫽ .30), including in a mea-
Figure 2 Summary of 30-day carotid stent outcomes in US high surgical⫺risk studies.
84 sure of quality of life (Multidimensional Index of Life Quality) although this data set was significantly incomplete. A larger Phase II CARESS trial has been planned but not yet initiated. Two randomized European studies published in 2006 have added to the data available for consideration, but not to the clarity of the place of carotid stenting vis-à-vis endarterectomy. The SPACE trial was a randomized trial in symptomatic moderate-risk surgical patients with carotid lesions ⬎50% (according to the NASCET criteria) conducted in Germany, and was sponsored by several institutions and companies. Three carotid stent systems and five embolic protection systems were approved for use in this trial based on their Communite European (CE) mark availability, and the primary endpoint of the study was ipsilateral stroke and death from any cause at 30 days. The statistical design of the trial called for a 2.5% noninferiority margin assuming a true event rate of 5% in each group and, based on a 5% alpha and 80% power, 950 patients were needed per treatment group. Prespecified interval analyses were performed, as well as subgroup analyses according to age and gender at the completion of the trial. Important to note in this trial, only 27% of patients in the stent arm had embolic protection devices used. The SPACE steering committee stopped the study after enrolling approximately 1,200 patients between 2001 and 2006, based on a second interim analysis suggesting at the observed event rate and actual difference in the therapies that more than 2,500 patients would be required to demonstrate noninferiority, for which the required funding was lacking. Nevertheless, results between the two groups were similar, with a 30-day primary endpoint of 6.34% versus 6.84% (P ⫽ .09). Recently, prespecified analysis demonstrated a significant differential in outcomes according to age for stenting, but not for surgery, which maintained a roughly 6.5% ageindependent event rate. A regression tree analysis gave a separation of outcomes for stenting at 68 years, ie, 2.7% 30-day events under the age of 68 years and 10.8% when older. This translated into an advantage for stenting over surgery in the younger age group.10 In summary, SPACE appears to show near equivalence for the overall cohort of ⬃1,200 symptomatic patients, in spite of a lack of embolic protection in a significant majority of subjects. Failure to achieve noninferiority was the result of unanticipated increases in the total number of patients required and a lack of commensurate funding, but not due to safety or futility concerns. Differential outcomes by age suggest that future trial results should be analyzed accordingly. The Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial11 was conducted in France between 2000 and 2005 and was sponsored by the French government. The trial inclusion was very similar to SPACE. Recently symptomatic patients of moderate surgical risk and carotid stenosis ⬎60% (NASCET criteria) were randomized 1:1 between stenting and surgery, with a 30-day primary endpoint of any stroke or death. In a similar time period, however, EVA-3S enrolled less than half the number of patients in SPACE. The study was stopped after
W.A. Gray 527 patients were randomized on the basis of safety and futility. The primary endpoint was seen in 9.6% of stent and 3.9% of endarterectomy patients (P ⫽ .01). A close look at the trial conduct, however, suggests significant deficiencies in training and low-volume stent operators, which resulted in heretofore unheard of rates of emergency surgery (5% resulting in two strokes, whereas few if any of the ⬎3,000 US pivotal trial patients went to emergency surgery). There was no centralized certification body to assess the preparedness of operators: surgeons had to have performed 25 endarterectomies in the year before enrollment, but a stent operator could have as few as five lifetime procedures to be considered qualified, but no oversight as to use of protection systems or outcomes in those procedures was undertaken. A first-time stenter was permitted to randomize patients under the tutelage of such a qualified operator and, of the sites involved in EVA-3S, two-thirds were under such tutelage at the start of their randomized participation. In addition, the late entry of embolic protection devices, which were mandated after four to five excess strokes in the stent arm during a protectionoptional phase, also may have contributed to excess strokes in the stent group. Nonstandard practices, such as significant use of anesthesia in ⬃30% of patients (estimated ⬍5% in the United States) and lack of predilation before stenting also had unclear effects on outcomes. In summary, the disparate results of these two trials (EVA-3S and SPACE) and glitches in their design and conduct leave the question as to the place of stenting in the management of symptomatic patients at reasonable risk for surgery unanswered. It may very well be that these results are reflective of the true results of stenting, but conclusions in this regard would be difficult to reach based on SPACE and EVA-3S alone. Nevertheless, these highly publicized, albeit flawed, trials have had a real effect on stenting in the United States, based on their publication in the Lancet and the New England Journal of Medicine, and new data will likely be required to change the perception of the therapy.
Data Since Device Approval PMS study data since device approval have been both remarkably plentiful as well as valuable. As a condition of all new device approvals, the FDA stipulates a PMS program be established to identify any rare or unanticipated device-related events (frequency ⬍1%). In case of carotid stenting, the ability to demonstrate the transfer of the technology and technique from the clinical trial setting to the “real-world,” and hence the adequacy of training programs proposed by manufacturers and approved by the FDA was also an important goal of the PMS registries. Important to any discussion of these data is an understanding of the conduct of these studies. In the Carotid Artery Stenting With Emboli Protection Surveillance Post-Marketing Study (CASES-PMS),12 Carotid RX ACCULINK®/RX ACCUNET™ Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE),13,14 Emboshield® and Xact™ Post Approval Carotid Stent Trial (EXACT), and CAPTURE 2 studies, data were collected prospectively, all patients underwent independent neurologic
Clinical trials: past, present, and future
85
Figure 3 Temporal Improvement in CAS Outcomes Since Initial FDA Device Approval in 2004.
evaluation before and after the procedure and again at 30 days, and results were then adjudicated by an independent Clinical Events Committee. These registries have been extended beyond the originally mandated 1,500 patients per manufacturer, and now have data on well over 10,000 patient outcomes. Accordingly, these registries represent the largest multicenter, prospective, neurologically controlled, and adjudicated data sets carotid revascularization therapies ever assembled. Published results of both CASES and CAPTURE registries confirmed that there were no unanticipated device-related events, and that the transfer of the technology to the nontrial larger-scale environment was successful, thereby validating the training programs established by the device manufacturers. Not only were the outcomes of these postapproval studies initially better than even the predicate pivotal trials (SAPPHIRE and ARCHeR), but in the case of the Abbott Vascular data sets, there has been a continuous temporal improvement in the results during the 3 years since broad application postapproval (Fig 3, unpublished data). This is especially relevant because after the landmark NASCET and Asymptomatic Carotid Atherosclerosis Study (ACAS) trials in endarterectomy, 30-day mortality measured in more than 100,000 patients was nearly threefold greater when the surgery was performed outside the trial setting, even in trial hospitals.15 In addition to achieving the stated goals, the PMS registries have provided a wealth of information about the procedure not otherwise available from the much smaller pivotal device-approval trials because they were powered for endpoints typically requiring only 300 to 500 patients, which did not allow any significant subset analysis. Some of the important observations from these registries include: 1. Predictors of adverse outcomes in carotid stenting include:
a. Advanced age (older than 80 years); although this finding is in keeping with most other surgical and interventional procedures, the most recent unpublished data suggest the differential in outcomes in stenting as a function of age is narrowing.12,13 b. Symptomatic patients; similar to endarterectomy symptomatic patients, appear to have not only the greatest benefit from the procedure but also the greatest risk. Different from endarterectomy, patients receiving carotid stenting within the first 2 weeks after symptoms appear to have a roughly twofold increase in outcomes compared to those stented after this initial period.13 This may speak to the temperament of the symptomatic plaque after presumed rupture caused the original symptoms. c. Use of either multiple stents or balloon predilation prior to placement of the embolic protection device. These might be markers of operator inexperience or lesion complexity, or both.13 2. Approximately 20% of all strokes occurring in carotid stenting (an absolute rate of ⬃1%) occur in a nonipsilateral vascular territory; this remained true regardless of the age of the patient, the symptomatic status of the patient, or the experience of the operator.14 It suggests an access-related cause, creating an opportunity to improve outcomes with either better technique or equipment. 3. Approximately one-third of all strokes in carotid stenting are observed more than 24 hours after the procedure. Although the explanations for this finding range from late embolic events to delayed clinical onset of symptoms, they remain speculative. Lastly, the PMS registries for CAPTURE 2 and EXACT, representing the most contemporary data available, demonstrate the achievement of the 3% goals for asymptomatic
W.A. Gray
86 populations outlined by the American Heart Association in their 1998 Guidelines for Endarterectomy. This same goal has never been demonstrated in the high surgical⫺risk population with endarterectomy in a prospective, multicenter, adjudicated survey.
Future Trials The place of carotid stenting in the high surgical⫺risk patient appears to be solidifying, as more data emerge, but the question as to the application of this procedure in the much larger population of standard-risk patients remains unanswered. Two important US trials are currently underway that will add to the increasing understanding of carotid stenting in this population. The CREST trial is a cosponsored trial between the NIH/ National Heart, Lung and Blood Institute and Abbott Vascular, and is randomizing patients with both symptomatic and asymptomatic carotid stenosis who are good surgical candidates for either stenting or endarterectomy in a 1:1 ratio. Started in the late 1990s, with the first randomized patient in December 2000, CREST is now enrolling in more than 110 sites in the United States and Canada, and is approximately 200 patients away from completing its 2,500 patient enrollment; it is projected to be completed in mid-2008. The primary endpoint is 30-day death, stroke, and myocardial infarction plus ipsilateral stroke to 1 year; the trial also acts as an IDE for the devices being used (ACCULINK stent and ACCUNET filter), assuming noninferiority is achieved. The trial was designed well before many of the observations listed previously from the pivotal and PMS studies better characterized carotid stenting, so there may be analyses that would otherwise be prespecified (such as time from symptom to procedure) that will not be included in the initial analysis. Nevertheless, data from this large trial will significantly add to our knowledge base on the relative merits of these two types of carotid revascularization. ACT I is an Abbott Vascular⫺sponsored study randomizing standard-surgical risk asymptomatic patients only to either stenting with the EXACT stent and the Emboshield filter or endarterectomy in a 3:1 ratio. The trial has an endpoint of 30-day death, stroke, and myocardial infarction plus ipsilateral stroke to 1 year. Currently, there are approximately 500 patients entered in this trial, which began in 2005, and anticipated enrollment is approximately 1,800 patients. The Transatlantic Asymptomatic Carotid Intervention Trial (TACIT) study has been in development for several years and although initially rejected for NIH funding, contains an optimal/modern medical therapy arm in addition to revascularization arms in order to address the question raised by many stroke neurologists who point out that none of the trials of surgery or stenting have adequately treated their noninterventional arm with targeted medical therapy, although there is a lack of data for stroke prevention with these therapies in patients with established severe carotid disease. TACIT would hope to answer this concern, and is being formulated as a trans-Atlantic endeavor. ACST 2 (asymptomatic patients) and CAVATAS 2 (symp-
tomatic patients) are both European efforts underway as follow-up to the original studies, this time with express purpose of assessing carotid stenting rather than medication and angioplasty, respectively, compared to surgery.
Summary Carotid stent trial data developed to date as a result of these and other trials eclipse that available in endarterectomy in terms of the prospective, multicenter, and independent assessment of the technology, and compares well in the high surgical⫺risk population. However, because such a population was never clearly defined until carotid stenting came along, carotid stenting remains controversial in this group of patients by those who either do not believe such a population exists in spite of data to the contrary, or does not benefit from any revascularization, surgical or stenting. It likely will remain a procedure with limited patient access until investigation definitively proves its value as compared to endarterectomy in the standard-risk population. Several studies currently underway will hopefully make the technology more available to a broader base of patients who generally prefer nonsurgical methods, assuming equal safety and efficacy.
References 1. Rothwell PM, Slattery J, Warlow CP: A systematic review of the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis. Stroke 27:260-265, 1996 2. CAVATAS Investigators: Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 357:1729-1737, 2001 3. Barnett HJM, Taylor DW, Eliaszaw M, et al: Benefit of carotid endarterectomy in patients with symptomatic carotid stenosis. N Engl J Med 339:1415-1425, 1998 4. The European Carotid Surgery Trialists’ Collaborative Group: Endarterectomy for moderate symptomatic carotid stenosis: interim results from the MRC European Carotid Surgery Trial. Lancet 347:1591-1593, 1996 5. Yadav JS, Wholey MH, Kuntz RE, et al: Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 351:14931501, 2004 6. Gray WA, Hopkins LN, Yadav S, et al: Protected carotid stenting in high-surgical-risk patients: the ARCHeR results. J Vasc Surg 44:258269, 2006 7. Iyer SS, White CJ, Hopkins LN, et al: Carotid artery revascularization in high-surgical-risk patients using the carotid Wallstent and FilterWire EX/EZ. J Am Coll Cardiol 51:427-434, 2008 8. Safian RD, Bresnahan JF, Jaff MR, et al: Protected carotid stenting in high-risk patients with severe carotid artery stenosis. J Am Coll Cardiol 47:2384-2389, 2006 9. CARESS Steering Committee: Carotid revascularization using endarterectomy or stenting systems (CARESS): phase I clinical trial. J Endovasc Ther 10:1021-1030, 2003 10. Stingele R, Berger J, Alfke K, et al: Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent-protected angioplasty: a subanalysis of the SPACE study. Lancet Neurol 7:216-222, 2008 11. Mas JL, Chatellier G, Beyssen B, et al: EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 19:355:1660-1671, 2006 12. Katzen BT, Criado FJ, Ramee SR, et al: Carotid artery stenting with
Clinical trials: past, present, and future emboli protection surveillance study: thirty-day results of the CASES-PMS study. Catheter Cardiovasc Interv 70:316-723, 2007 13. Gray WA, Yadav JS, Verta P, et al: The CAPTURE registry: predictors of outcomes in carotid artery stenting with embolic protection for high surgical risk patients in the early post-approval setting. Catheter Cardiovasc Interv 70:1025-1033, 2007 14. Fairman R, Gray WA, Scicli AP, et al: The CAPTURE registry: analysis
87 of strokes resulting from carotid artery stenting in the post approval setting: timing, location, severity, and type. Ann Surg 246:551-556; discussion 556-558, 2007 15. Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES: Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA 279: 1278-1281, 1998