MedIntelliBase® NewsTips     January 2007

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Table of Contents
1) UPDATE - Late Thrombosis & other topics on Drug-Eluting Stents (DES)
  • Summary DES issues:
    • 1a) The December 2006 FDA panel's findings on late thrombosis >> click here
    • 1b) Continued research in DES and vessel healing >> click here
    • 1c) Preliminary findings - Impaired collateral flow linked to DES >> click here
2) Carotid Therapeutics & Stroke Prevention
3) New MedIntelliBase Alerts 
4) Link of the Month
  • Angiogenesis - A definition, historical highlights, facts & figures and more...
5) Healthy Advice for the Month

6) MedIntelliBase Alerts & MarketTracks >>
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1) Drug-eluting stents (DES) - is there additional risk of late stent thrombosis when compared with bare metal stents (BMS)?

In light of continued developments regarding the long-term safety of drug-eluting stents, The Next Phase continues its coverage of DES late thrombosis and other emerging issues expanding our prior MIB NewsTips discussion of October 2006:

1a) UPDATE - Is there additional risk of late stent thrombosis when compared with bare metal stents (BMS)?

FDA Panel Meeting, December 2006-
On December 7 & 8, 2006, the FDA convened a panel meeting to fully characterize the risks, timing and incidence of DES thrombosis, and to address the appropriate duration of clopidogrel use in DES patients.

Medical device companies are taking these findings seriously. DES makers are actively implementing the panel's recommendations including label changes that reference the recommended dual antiplatelet therapy, and further research is underway to solve the problem of late thrombus formation.

A summary of the panel's findings follows:
  • There was a general agreement that DES, when used in accordance to their FDA approved labeled indications, are associated with a clinically important numerical excess of late stent thromboses (1 year post-implantation) compared to BMS; however, the magnitude of this excess is uncertain and additional data are needed.
  • Based on the analyses presented by Boston Scientific and Cordis, it was concluded that DES are not associated with an increased risk of death or myocardial infarction (MI) compared to BMS, despite an apparent increase in stent thrombosis rates after 1-year post-DES implantation. This finding may be due to (1) insufficient sample size in currently available studies; or (2) that an increase in death and MI secondary to DES thrombosis might be offset by a reduction in death and MI associated with in-stent restenosis and additional revascularization procedures in DES patients.
  • The panel agreed that when compared to BMS, DES are not associated with an increased rate of all-cause mortality. The panel requested longer-term follow-up and an increased number of patients in future trials.
  • The panel was in agreement that the safety concerns discussed applied equally to the currently approved DES.
  • The panel reached consensus that the DES safety concerns do not outweigh their benefits compared to BMS when used within the limits of the approved labeling.
  • The panel discussed different options to modifying the labeling for the approved DES.
  • The panel was in consensus that the DES labeling should reference the ACC/AHA/SCAI PCI Practice Guidelines for duration of antiplatelet therapy following DES implantation.
  • The Panel recognized that with more complex patients, there is an expected increased risk in adverse events in these subsets. The panel generally agreed that off-label use of DES is associated with an increased risk of stent thrombosis, death and MI when compared to on-label use of DES. The Panel did not find sufficient data were available to identify subsets of patients as at a particularly increased risk.
  • The panel agreed that at least 12 months of dual antiplatelet therapy should be recommended for off-label uses of DES.
  • The panel was unanimous that insufficient available data precluded an opinion regarding whether concerns related to off-label use were similar between the currently approved DES.
  • The panel was in agreement that the data on off-label use are limited and recommended that the DES labeling state that results from off-label use of DES should not necessarily be expected to be the same as the results from the clinical trials conducted to support marketing approval.
  • The panel called for larger and longer premarket clinical trials and longer follow-up for post-approval studies, with specific definitions related to stent thrombosis events, and more attention paid to patient monitoring and patient compliance with antiplatelet therapy.

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1b) DES and Vessel Healing

Restenosis is Checked - Is Longer Term Vascular Healing at Risk?

DES significantly reduce the possibility of restenosis, but can also lead to delayed or incomplete vascular healing. Dr. William Wijns, MD has presented an overview of current 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 DES led to inflammation, allergic reactions and lack of endothelialization. He also noted that bare metal stents and DES appear to induce different responses. Functional studies of endothelium-dependent vasomotion show 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 today's commercially available DES (0.53%) and BMS (0.53%). A head-to-head study between the Cypher and Taxus stents shows 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.

Planned Studies-
Appropriately, three new studies have been announced 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, notes 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.
Predictors of Stent Thrombosis-
With these issues in mind, recall the independent predictors of cumulative stent thrombosis as reported in the May 4, 2005 issue of 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.

A study presented at TCT06 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. Renu Virmani, FACC, a pathologist and medical director of CVPath, International Registry of Pathology, Maryland, 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.

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1c) DES and Impaired Collateral Flow

Preliminary findings-
A second and compounding result of the over-effectiveness of DES drugs may be a reduction in collateral coronary blood flow. A recent article published in the January 2, 2007 issue of Journal of the American College of Cardiology describes how DES can compromise small blood vessel function.

Dr. Pascal Meier, University Hospital, Bern, Switzerland, et al., explain that the positive effects of DES on restenosis are possibly attained at the price of toxic vascular injury leading to a delayed healing of the traumatized vessel wall. The researchers studied 120 patients who received either BMS or DES and measured the development and proliferation of functional small vessels near the stent. They determined that collateral function was 30% to 40% lower in patients who received a DES vs. a BMS.

In the event of stent thrombosis, collateral coronary vessels protect the myocardium from ischemia. Impaired collateral function in patients with prior DES placement could worsen the consequences of an acute coronary occlusion. In an editorial to the Swiss paper, Dr. Morton Kern, chief of cardiology at the University of California-Irvine, describes collateral vessels as "nature's little bypass." These channels are usually present only when normal pathways are blocked by coronary artery disease. Meier's research found that usual collateral development is impaired in patients with DES. Previous studies support this hypothesis and show that six-month mortality following BMS thrombosis is 11% to 21%, while 29% to 45% in DES patients.

The researchers found that there was not a statistical difference in this negative collateral effect between sirolimus or paclitaxel stents. This finding points to the idea that impaired collateral function is a result of a broader function not specific to either drug. Given the nature of this evidence is preliminary at this time, Editor-in-Chief of JACC Anthony deMaria, MD, stated, "the effect of impaired collateral formation upon the outcome of acute stent thrombosis is speculative."

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2) Carotid Therapeutics & Stroke Prevention

Safety and Efficacy of Carotid Artery Stenting (CAS)-
In the aftermath created by the publication of the EVA-3S and SPACE trials there has been recent affirmation of the safety and efficiency of carotid artery stenting (CAS). During the week of January 2 – 9, 2007,  the Journal of the American College of Cardiology published an expert consensus document, a thorough update on CAS procedures. The JACC article details pharmacological, surgical and percutaneous modalities for the treatment of coronary artery disease. Guidelines for CAS procedures were also recommended.

Perhaps the most interesting aspect of the article is found near the end of the document. The author’s concluding remark considers the most recently developed devices and supporting clinical trials for CAS in both high and low-risk patients, and suggests it may become the treatment modality of choice for patients who are candidates for CEA. Other recent publications have supported this conclusion, detailing the safety and efficiency of CAS procedures. One such article of note is the follow-up analysis of data from the CAPTURE trial.

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4) Link of the Month
  • Angiogenesis - Your body's control, its role as a common denominator in disease, a history, facts & interesting look at angiogenesis. [The Angiogenesis Foundation]
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5) Healthy Advice for the Month
This month we forgo our regular Fun Fact to bring this healthy tip to you...
  • Are you a diet cola drinker? - A recent study has suggested that consuming 3 cola soft drinks per day may lead to bone loss in women... [WebMD]
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Market Research Analyst: Jordan Zornes
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© The Next Phase® Consultancy, Inc. 2007. All rights reserved.

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