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Table of Contents --  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
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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:
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:
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:
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. Interested in keeping up to date on this issue? Is there another specific area of interest where you need current, timely information? Click here to learn more about our MIB Alerts and MarketTracks - A Better Way to stay up to date. Return to Top |
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