MedIntelliBase® NewsTips
    31 October 2006


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Late-Breaking Updates

Drug-eluting stents (DES) Late Thrombosis - Is there additional risk when compared to Bare Metal Stents (BMS)?


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Late-Breaking Updates
Transcatheter Cardiovascular Therapeutics (TCT) 2006 - Clinical trial and emerging technology updates from the late October TCT 2006 conference in Washington, D.C.

All updates expand your access to our extensive archives of pivotal trials and registries as well as emerging and established technologies.
    Cardiovascular Therapeutics
  • LONG-DES-II trial - Cypher sirolimus-eluting stent vs. Taxus paclitaxel-eluting stent
  • ABSORB trial - Bioabsorbable Vascular Solutions (BVS) everolimus-eluting stent
    Carotid Therapeutics & Stroke Prevention
  • EVA-3S trial - Carotid Wallstent & FilterWire EZ, Acculink & Accunet, Precise RX & Angioguard RX, the Zilver, GuardWire Plus and the Spider & Spider RX
  • SPACE trial - Carotid Wallstent & FilterWire EX, Precise & AngioGuard, Acculink, PercuSurge GuardWire, NeuroShield, and Carotid Trap

    Cardiovascular Therapeutics

  • LONG-DES-II trial
    The Long-DES-II (Percutaneous Treatment of LONG native Coronary Lesions with Drug-Eluting Stent-II: Cypher versus Taxus) trial compared the efficacy of the Cypher sirolimus-eluting stent to the Taxus paclitaxel-eluting stent in the treatment of long coronary lesions (>25 mm, planned total stent length ≥32mm). This 1:1 randomized, controlled study evaluated 500 patients and had a primary endpoint of angiographic restenosis at 6 months. In-segment, in-stent and distal edge restenosis rates were significantly lower with the Cypher stent vs. the Taxus stent, while proximal edge restenosis rates were not significantly different.
  • ABSORB trial
    The ABSORB (Bioabsorbable Vascular Solutions (BVS) EECSS First in Man Clinical Investigation: A Clinical Evaluation of the BVS Everolimus Eluting CSS in the Treatment of Patients With Single De Novo Native Coronary Artery Lesions) study is designed to assess the safety and performance of the BVS everolimus-eluting coronary stent system in 30 patients with single, de novo, native coronary artery disease. 30-day results demonstrate that the stent is safe and deployed with a high procedural success rate (100%). A high device success rate (93.5%) and a low MACE (Major Adverse Coronary Events) rate (0%) were observed. This study also demonstrated that relative stent recoil of the polylactic acid (PLA)-based stent does not significantly differ between the BVS stent and the XIENCE V metal stent.
    Endovascular Therapeutics

  • FAST trial
    The FAST (Femoral Artery Stenting Trial) was designed to assess the efficacy of the Bard Luminexx 3 vascular stent vs. balloon angioplasty (PTA) in 224 patients with superficial femoral artery (SFA) disease. The study's primary endpoint was binary restenosis at 12 months. This study did not demonstrate the superiority of the Luminexx stent over PTA in terms of the primary endpoint in SFA lesions 1 to 10 cm in length. However, stent placement appeared to be associated with a tendency towards a lower risk of restenosis in a wide variety of patient and lesion subgroups, warranting further prospective randomized trials in these patient cohorts including diabetics and patients with total occlusions.
  • Rotational Atherectomy Device for Recanalization of Infrainguinal Lesions
    This study evaluated the Pathway Atherectomy system for primary atherectomy of occlusions and stenoses > 70% on infrainguinal lesions with a reference diameter of 3.0 to 5.0 mm. A total of 22 patients with 26 lesions (22 stenoses and 4 occlusions) were treated with a mean degree of stenosis of 93% in the superficial femoral artery, the popliteal artery and infrapopliteal arteries. Additional low-pressure balloon angioplasty was performed in 15 lesions (58%), and there was no need for additional stenting. According to initial data, the Pathway Atherectomy system is both safe and clinically effective; in all cases there was a marked clinical improvement.
    Carotid Therapeutics & Stroke Prevention

  • EVA-3S trial
    The EVA-3S (Endarterectomy Versus Angioplasty in Patients with Severe Symptomatic Carotid Stenosis) trial was ultimately a non-inferiority trial comparing carotid artery stenting (CAS) with the established surgery of carotid endarterectomy (CEA). High stroke, death and adverse event rates in the CAS patient group let to an early termination of the trial. There is much controversy regarding the methods used in terms of operator experience, device choice, cerebral protection and CEA bias. The CREST trial currently underway in the United States is seen to be a comparable study with sharp differences on the aforementioned issues. EVA-3S used the Boston Scientific Carotid Wallstent (Monorail and OTW) and FilterWire EZ, Abbott Acculink and Accunet, Cordis Precise RX and Angioguard RX, the Cook Zilver, Medtronic GuardWire Plus and the ev3 Spider and Spider RX. This trial was published on October 19, 2006 in the New England Journal of Medicine.
  • SPACE trial
    The SPACE (Stent-Protected Angioplasty versus Carotid Endarterectomy in symptomatic patients) trial in an ongoing non-inferiority study of carotid artery stenting (CAS). The trial was designed to show that CAS was not inferior to carotid endarterectomy (CEA) in less than high risk patients. Inclusion criteria include at least 50% stenosis as defined by the NASCET trial. As of the 30-day results published on October 7, 2006 in the Lancet, CAS had not proved non-inferior to CEA. All devices used were required to have a CE mark. SPACE is using the Boston Scientific Carotid Wallstent and FilterWire EX, Cordis Precise and AngioGuard, Abbott Acculink, Medtronic PercuSurge GuardWire, MedNova NeuroShield, and Microvena Carotid Trap.
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These MedIntelliBase™ MarketTracks titles are newly updated:
  • Cardiovascular (CV) Therapeutics
  • Endovascular (EV) Therapeutics
  • Carotid (Carotid) Therapeutics & Stroke Prevention
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Drug-eluting stents (DES) - is there additional risk of late stent thrombosis when compared with bare metal stents (BMS)?

In light of controversial studies and presentations regarding the long-term safety of today's drug-eluting stents, most recently at the Transcatheter Cardiovascular Therapeutics (TCT) 2006 meeting, The Next Phase presents a brief summary of these developments as an expansion of our discussion from this month's special-edition newsletter:

Overview-
DES significantly reduce the possibility of restenosis, but can also lead to delayed or incomplete vascular healing. Dr. William Wijns, MD presented at the TCT06 meeting an overview of safety concerns with DES, and a timeline and predictive factors for stent thrombosis (discussed below). Dr. Wijns noted that post-implantation delayed healing is observed with DES up to one year, and that up to two years sequential IVUS virtual histology has demonstrated that plaque size can change behind stent struts.

According to Dr. Wijns' presentation DES lead to inflammation, allergic reactions and lack of endothelialization. He also noted that bare metal stents and DES appear to induce different responses. For example, he cited functional studies of endothelium-dependent vasomotion showing abnormal vasoconstriction with DES, but not BMS. In terms of stent thrombosis, Dr. Wijns described that BMS and DES exhibit similar characteristics during the first month, within which thrombosis generally occurs early and there is no significant difference between the two stent varieties. This trend continues as there is no significant difference in late stent thrombosis up to one year for todays commercially available DES (0.53%) and BMS (0.53%). Dr. Wijns cited a head-to-head study between the Cypher and Taxus stents showing no difference in late stent thrombosis rates between the two.

Dr. Wijns suggests that one must look beyond one year to find that "very late" stent thrombosis occurs more frequently in DES vs. BMS, although to better understand this issue more adequate trials are necessary. He suggests a consensus on study endpoints and their definitions, independent data analysis of all patient data, and adequately-sized trials focusing on safety, efficacy and quality of life endpoints.

New Studies-
Appropriately, three new studies were announced at the TCT06 meeting to help better characterize the long-term effects of DES. Gregg Stone, MD, Chairman of the Cardiovascular Research Foundation and Professor of Medicine at Columbia University Medical Center in New York, noted that these studies are needed to better understand the risks and benefits of DES treatment. The announced studies include:
  • STENT Thrombosis - This study will examine 10,000 consecutive DES patients at 12 centers as compared to 30,000 control patients. A two to five year follow-up period is planned.
  • INSIGHT - This 30,000-patient global registry will look at the use of standard versus long-term clopidogrel use in DES patients.
  • PROTECT - This study will compare the Endeavor (Medtronic) DES to the Cypher (Cordis / J&J) DES in a randomized, international trial of 8,000 patients with a primary endpoint of in-stent thrombosis.
Controversial Data: More Stent Thrombosis Risk-
Dr. Renu Virmani, FACC, a pathologist and medical director of CVPath, International Registry of Pathology, Maryland, has voiced the possibility of problems with widespread DES use for several years, and with her colleagues has recently published findings in the Journal of the American College of Cardiology (2006;48:193-202). She warns that in real-world practice patients are often times more complex than those observed in initial DES approval trials. In real-world patients the risk of late thrombosis resulting from DES use is increased over bare metal stents (BMS). A recent (October 27, 2006) interview with Dr. Virmani can be found in The Boston Globe.

Several studies support the sentiments of Dr. Virmani, including the BASKET LATE trial (Late Clinical Events Related to Late Stent Thrombosis After Stopping Clopidogrel) discussed here and a second meta-analysis described below. BASKET LATE results reported at the 2006 American College of Cardiology (ACC) meeting showed that there is a significant increase in the incidence of cardiac death or MI in DES patients (n=499) as compared to BMS patients (n=244) following the discontinuation of clopidogrel (cardiac death or MI: 4.9% vs. 1.3%, p=0.01; MI: 4.1% vs. 1.3%, p=0.04). These clinical events are thought to be often related to stent thrombosis, however there was no statistically significant difference between DES and BMS patients (2.6% vs. 1.3%, p = 0.23) despite late stent thrombosis occurring twice as often in DES patients.

Results from a meta-analysis of first-generation DES versus BMS presented at the 2006 European Society of Cardiology (ESC) meeting focused on rates of death or Q-wave MI. All available data from manufacturer-supported randomized trials were evaluated including 878 sirolimus-eluting stent (SES) patients and 1,685 paclitaxel-eluting stent (PES) patients. The rate of death or Q-wave MI in SES patients was significantly higher than BMS patients (6.3% vs. 3.9%, p=0.03), and though not statistically significant a higher rate of death or Q-wave MI was observed in PES patients (2.6% vs. 2.3%, p=0.68).

Controversial Data: Similar Stent Thrombosis Risk-
On the other hand, DES manufacturers Boston Scientific and Cordis have recently emphasized data maintaining the safety and effectiveness of their respective drug-eluting stents. For example, Boston Scientific notes that the 3-year cumulative data from TAXUS pivotal trials (II and IV) demonstrate no statistically significant increase in death and MI (5.7%) versus BMS (5.3%, p=0.63) for the TAXUS Express stent. 3-year cumulative data from the RAVEL, SIRIUS, and E-SIRIUS trials also demonstrate no significant increase in death and MI (6.0%) versus BMS (4.0%, p=0.06) for the Cypher stent. These data help support the claim that the risk vs. benefit ratio are in favor of DES as very similar safety outcomes are observed with a significantly reduced rate of Target Lesion Revascularization (TLR).

Dr. Stone conceded at the TCT06 meeting that DES may have side-effects including an increased incidence of late stent thrombosis in about two to four patients per 1,000 per year. However, he suggested that recently-reported controversial data suggesting this may have severe limitations, including limited follow-up. This limitation may have increased the chance of patients who entered the trial presenting with adverse events. He added that other current studies suggest that DES do not increase overall death and MI rates, and suggested that DES use should not be discontinued as a result of early reports. Dr. Stone said that the risks and benefits of using DES should be carefully considered on a per-patient basis, especially if off-label use is considered. Despite the recent controversy he reasoned that the benefits of DES are still extensive, including restenosis prevention, reduced repeat treatment rates, fewer coronary artery bypass graft (CABG) surgeries and an improved quality of life for millions of patients.

Dr. Donald Cultip of the Harvard Clinical Research Institute, Boston, MA, presented data at TCT06 suggesting that results from a meta analysis of trials suggesting a significant 0.4% to 0.6% increase in risk of late stent thrombosis with DES compared to BMS can be questioned. A new definition for stent thrombosis developed by the American Research Consortium was presented by Dr. Cultip and designed to eliminate variability in definitions among DES trials. The proposed definition defines three types of stent thrombosis:
  • Definite: stent thrombosis that has been confirmed by angiography or when pathologic confirmation of acute thrombosis in Acute Coronary Syndrome (ACS) patients is made
  • Probable: any unexplained death within 30 days, or target vessel MI without angiographic confirmation of thrombosis or other identified culprit lesion
  • Possible: unexplained death after 30 days
Based on this new definition, Dr. Cultip reported that an analysis of the RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS trials demonstrated that the risk of stent thrombosis out to four years in patients with Cypher stents was not significantly different from the risk in patients who received BMS. Using the new definition, stent thrombosis occurred in 3.5% of the DES arm and 3.3% in the BMS arm. A further analysis of definite or probable stent thrombosis showed a 1.7% risk in the BMS arm and a 1.5% risk in the DES arm.

FDA's Position-
On September 14, 2006 the FDA released a statement noting that it believes DES remain safe and effective when used for the FDA-approved indications. The FDA mentions in its statement that it has been closely monitoring DES since they were approved in 2003, and acknowledges that new data has recently suggested a small, significant increase in the risk of stent thrombosis following DES placement.

While important questions have been raised by the new data, the FDA states there is not enough information to draw conclusions on the rate or cause of DES thrombosis, the circumstances under which it occurs, or the risk of occurrence in a given patient. In addition to meeting with Cordis and Boston Scientific, the FDA plans to convene a public panel meeting of outside scientific experts to thoroughly review all data and consider recommendations about appropriate actions, including possible additional studies or labeling changes. This meeting is scheduled to take place December 7-8, 2006 in Washington, D.C. The FDA has requested that the American Research Consortium's new definition of stent thrombosis (provided above) be used at this meeting.

Predictors of Stent Thrombosis-
With these issues in mind, recall the independent predictors of cumulative stent thrombosis as reported in the Journal of the American Medical Association (2005;293:2126-30). They include:
  • Premature discontinuation of antiplatelet therapy
  • Renal failure
  • Bifurcation lesion>
  • Diabetes
  • Low LVEF
More specifically, stent length is a predictor of subacute stent thrombosis, while neither renal failure nor diabetes predicts late stent thrombosis.

Dr. Wijns described a study during TCT06 that assessed the univariate predictors of cumulative stent thrombosis as premature antiplatelet therapy discontinuation (29%), prior brachytherapy (8.7%), renal failure (6.2%), bifurcation with two stents (3.9%), bifurcation lesion (3.6%), unprotected left main (3.3%) and diabetes (2.5%). It is also speculated by Dr. Virmani and others that late stent thrombosis could be linked to local over-effectiveness of drugs at specific sites where endothelialization does not occur. She has stated that compared to variables such as stent length, the number of uncovered struts is the best predictor of thrombosis in her studies.

DES Evolution-
Dr. Peter Fitzgerald, Professor of Medicine at Stanford University, noted at the TCT06 meeting that today we are looking for the safety of BMS and the efficacy of DES. He suggested that this mindset was also found during the introduction of angioplasty when early procedural difficulties prompted some to suggest moving toward medical treatment. Dr. Fitzgerald stated that today we are on the third hump where stent thrombosis is the issue causing people to rethink treatment with DES.

Dr. Fitzgerald suggests that next-generation DES should be able to balance endothelial coverage and function. The keys to next-generation DES success include three factors: medication, formulation, and endothelial platform. These factors are being considered by manufacturers of second generation DES such as Conor, Biotronik, and Medtronic.

Absorbable polymers, PC coatings that mimic red-blood cells, molecules to encourage endothelial healing and fully-absorbable stent struts are being developed to address these complex issues. Dr. Fitzgerald agrees with these approaches and suggested that the next revolution in DES will ultimately result in fully-biodegradable scaffolding.

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