The recent, first-time European presentation of the PERFORMANCE II trial’s findings—delivered by Ralf Langhoff (Sankt Gertrauden-Krankenhaus, Berlin, Germany) at the 2024 Charing Cross (CX) International Symposium (23–25 April, London, UK)—led delegates to discuss the role of stenting in carotid artery disease treatment, and how this has evolved in light of newer technologies.
Piotr Musialek (Jagiellonian University, Kraków, Poland) later noted that “the landscape has changed” recently, owing to the fact modern carotid stents are also ‘cerebral protectors’, while Christopher Metzger (OhioHealth, Columbus, USA) asserted that carotid artery stenting (CAS) is now competitive with carotid endarterectomy (CEA) when used appropriately.
In addition, while Musialek, Metzger and several other delegates were in firm agreement that there is still a place for surgery in carotid stenosis treatment, William Gray (Lankenau Medical Center, Wynnewood, USA)—global principal investigator (PI) for PERFORMANCE II—also suggested that “there aren’t really any controversies left” relating to CAS, and its ability to produce outcomes equivalent to CEA.
PERFORMANCE II in Europe
“The implications from the results of the PERFORMANCE II trial are that procedural embolic protection is the most important aspect in minimising stroke during CAS, and the Neuroguard three-in-one carotid stent system [Contego Medical] with 40-micron protection will be a transformational technology for the treatment of carotid artery disease.”
Those were the words of Langhoff, speaking to NeuroNews on the eve of CX 2024 to outline the significance of the study and its findings. Langhoff, who is the European PI for PERFORMANCE II, took to the CX podium during the Acute Stroke and Carotid Controversies programme on Wednesday 24 April to discuss these data in greater detail—a European first, following their initial presentation at last year’s Vascular Interventional Advances (VIVA) meeting (30 October–2 November 2023, Las Vegas, USA).
The prospective, multicentre PERFORMANCE II trial was set up to evaluate the safety and effectiveness of the Neuroguard integrated embolic protection (IEP) system, enrolling carotid disease patients with stenosis ≥50% if symptomatic or stenosis ≥70% if asymptomatic. According to Contego, the company behind this technology, the Neuroguard IEP system incorporates a novel, closed-cell nitinol stent, a balloon, and a filter with 40-micron pores, into a 6Fr device intended to capture micro-emboli and provide protection against stroke risks.
Langhoff’s podium-first presentation at CX saw him report low rates of minor (1.3%) and major (0%) stroke at 30 days across a total of 305 patients at 40 different clinical sites in PERFORMANCE II’s intention-to-treat (ITT) analysis, as well as a myocardial infarction (MI) rate of 0.7% and a death rate of 0.3%. He also relayed that no major strokes, contralateral strokes or neurological deaths ultimately occurred at 30 days.
Moving onto the trial’s primary endpoint (any stroke, death or MI at 30 days, and ipsilateral stroke from day 31 to 12 months), which was assessed across 282 patients at one year, Langhoff detailed a rate of just 2.8% in ITT analysis and 2.5% in the per-protocol analysis. The presenter went on to share rates of 3.7% for in-stent restenosis, 0% for neurological death, and 1.1% for target-lesion revascularisation, as per one-year ITT analyses. No major strokes nor instances of stent thrombosis occurred at one year either, according to Langhoff, and only one minor stroke was observed from day 31 to 12 months.
Putting these findings into context, Langhoff then pointed out that the 30-day ‘all stroke’ rate of 1.3% seen in PERFORMANCE II compares favourably to those observed with CEA in trials like ACST-2 (2.4%) and CREST 1 (2.3%), and is marginally better than in ACT 1 (1.4%) as well. This is especially notable, in Langhoff’s view, as all three of these studies included patient populations generally considered to be ‘standard risk’, while PERFORMANCE II exclusively enrolled patients deemed ‘high risk’ for CEA. The speaker further noted that similar trends were present regarding the primary endpoint outcome of PERFORMANCE II (2.8%), in comparison with the same measures for CEA in CREST 1 (6.6%) and ACT 1 (3.3%), at one year.
Langhoff’s concluding message was that—across a “challenging, high-risk” cohort of carotid artery stenosis patients—the PERFORMANCE II trial has demonstrated the durability, safety and effectiveness of the Neuroguard IEP system at both 30 days and one year. The presenter also averred that “these are the lowest one-year event rates reported for an adequately powered multicentre trial of any type of carotid revascularisation, regardless of patient risk”.
Stenting versus surgery
Discussions during the same session at CX 2024 also gave delegates—vascular surgeons, interventional cardiologists and neurointerventionists alike—a chance to address the current state of play in carotid disease treatment.
“I was asked to speak about carotid stenting controversies, and I would submit that there aren’t really any controversies left,” said Gray, alluding to the multitude of global trials, spanning high/low-risk and symptomatic/asymptomatic patients, that indicate “there’s really no difference between endarterectomy and stenting”. He cited data from more than 6,700 asymptomatic carotid artery stenosis patients across CREST 1, ACT 1, SPACE-2 and ACST-2, and a further 3,000 symptomatic patients from the CREST 1 and ICSS trials of 2010, to support the notion that transfemoral CAS appears to be at least equivalent to CEA.
While Gray went on to highlight comparable 30-day rates of any stroke/death/MI, and of major stroke, between CAS and CEA in seminal studies like CREST 1 and ACT 1, he did acknowledge lingering concerns over minor stroke rates, which were roughly twice as high with stenting in both trials.
“Where’s the controversy? I think it lies here,” Gray added. “I should note that minor stroke in these patients is typically recovered [from] within a week or two, and certainly by one month. Nevertheless, it’s not something we aspire to have.”
One of Gray’s key points subsequent to this was that “all is not lost”, as he drew the audience’s attention to the fact that—even prior to the technological advances seen in stenting over the past few years—improvements in patient selection and procedural techniques may have already instigated better CAS-related outcomes. Here, he referenced 2019 data from the CREST-2 registry, which reported “remarkable” stroke/death rates of 1.4% in asymptomatic and 2.8% in symptomatic patients; “about as low as has ever been reported [with] endarterectomy or stenting”.
The latest technologies
Two subsequent talks attempted to take a closer look at the technological advances alluded to previously by Gray.
Firstly, Musialek took to the podium, initially outlining the relevance of the timing of CAS-related stroke, as roughly 50% of strokes occurred post-procedurally in CREST-1, with a similar trend being observed in the 2007 CAPTURE trial and other large studies. The problem, according to Musialek, related to the limitations of the conventional, single-layer carotid stents being used in those early trials, and their inferior ability to fully eliminate plaque as compared to surgery.
“So, it’s not surprising that the key opinion leaders in vascular surgery said that—with the technology available at that time—CAS cannot be considered equivalent to CEA,” he noted. “But, if the technologies improve, we will come back and reevaluate.”
This provided a fitting introduction to discussions of several newer, second-generation ‘mesh’ carotid stents, such as the Hybrid Vascular Graft (Gore), the Casper/Roadsaver stent (Terumo), and the CGuard embolic prevention system (EPS; InspireMD). Musialek stated that, despite some similarities, these devices are mechanically different, and some of said differences may translate into varying clinical outcomes. However, he went on to highlight that recent studies have generally found significantly reductions in incidence of embolic material in filters, filter load, and CAS-related cerebral injury, with these newer-generation stents.
Musialek also drew attention to two meta-analyses—one comparing first- and second-generation carotid stents, and another comparing second-generation stents to contemporary CEA data—that have provided indications of the short- and long-term clinical benefits these more novel devices may enable.
“There is always a role for surgery,” he added, “but the landscape has changed. Today, patients need to be fully informed and involved in the decision of how they are revascularised, and the decision in a given centre should be determined by a multispecialty neurovascular team. Today’s carotid stents are cerebral protectors and, with respect to clinical decision-making, historical data have mostly historical value—we are treating patients today, not 20 years ago.”
A closing message from Musialek was that, in wider medicine, there is an “evolution” towards less invasive treatments, and this point was corroborated by Metzger during the session’s final presentation.
“Am I going to tell you that stenting is equivalent [to CEA] for every patient with obstructive carotid artery disease? Absolutely not,” he began. “In fact, it should only be performed if the patient has favourable anatomy and appropriate history for CAS, and the operator themselves is experienced, uses good technique, and has considered all options and considers stenting to be best. That said, CAS has matured to where it is an overall equivalent strategy, and this has developed under very close scrutiny for a long period of time.”
Metzger went on to posit that treatment strategies including CEA, CAS, and also best medical therapy, should be viewed as “complimentary, rather than competitive”, and emphasised the benefits of an individualised approach for each and every carotid stenosis patient.
Next, he touched on the fairly recent introduction of the aforementioned Neuroguard and CGuard stents, both of which have been specifically designed to reduce embolic events. In addition to once again highlighting “excellent” data from PERFORMANCE II, Metzger recapped the findings of the prospective, multicentre C-GUARDIANS trial evaluating the investigational CGuard device in 316 patients enrolled at a total of 25 US and European sites. He stated that—across a patient population that is, “by definition”, high-risk for endarterectomy, and 25% of whom were symptomatic—the study produced a 0.95% rate of stroke/death/MI at 30 days in its ITT analysis, and an event lower rate of 0.63% in per-protocol analyses. As with PERFORMANCE II, these findings were presented for the first time at VIVA 2023 and, according to Metzger, compare “very favourably” with historical endarterectomy outcomes.
“CAS is an excellent strategy, which is equivalent to the other options in well-selected patients treated by experienced operators—and new technology may lead to even better results,” Metzger concluded.
Attention is now likely to turn to upcoming results from trials assessing these ‘third-generation’ stent technologies. One-year, primary-endpoint data from C-GUARDIANS—pertaining to the incidence of major adverse events including any stroke/death/MI through 30 days post-index procedure, or ipsilateral stroke from day 31 to day 365 post-procedure—are expected later this year, and may instigate US Food and Drug Administration (FDA) approval of the CGuard device. In addition, while PERFORMANCE II saw Neuroguard placed via transfemoral or transradial access, the first patients have already been enrolled in the investigational device exemption (IDE) PERFORMANCE III study evaluating the same stent when implanted via direct transcarotid access.
