Taxus: Where Are We Now?Talking with Gregg Stone, MD

What questions still remain open about the Taxus stent? We certainly need long-term follow up, to make sure that the device is safe and effective over extended periods of time. From favorable long-term results of animal studies we expect that to be the case, but until we have 3-5 year data, we cannot be certain. As importantly, we need more studies and data in untested lesions and patients. There are lesions and patient types that were not included in TAXUS IV. Some of these are being studied in TAXUS V, including longer lesions, smaller vessels, larger vessels, overlapping stents and in-stent restenosis lesions in previously placed bare metal stents. However, we still have no significant data on patients with acute myocardial infarction, thrombotic lesions, bifurcation lesions, saphenous vein grafts, chronic total occlusions, left main disease, multi-vessel intervention, and so on. We need more registry and randomized studies to prove the safety and efficacy of the device in complex scenarios although we have no reason to think the Taxus stent would not be effective in those settings. Some of these issues will be addressed in the WISDOM, MILESTONE-2, TRUE, T-SEARCH and ARRIVE registries, as well as other randomized trials currently in the planning stages. You mentioned the TAXUS V trial, of which you’re the Principal Investigator. What’s the current status, and what is the status of TAXUS VI? The TAXUS V de novo study has completed enrollment, and will be presented next year sometime between the summer and fall. The TAXUS V in-stent restenosis study still has somewhat over 100 patients to randomize, with presentation anticipated for late 2005. TAXUS VI is a trial in 448 patients, which is complete. This trial used the moderate-rate release formulation of the TAXUS stent (as opposed to TAXUS V and VI, which utilized the slow-release formulation), and was restricted to long lesions, between 18 and 40 mm in length. TAXUS VI randomized such lesions to a bare metal Express stent versus the Taxus moderate-rate release stent. The 30-day data of TAXUS VI have been presented, and MACE rates were low in both groups. The 9-month data will be presented in May. What are you hoping to learn from some of the registries that are ongoing, like ARRIVE? Firstly, we’re going to learn if there are any safety concerns when TAXUS is translated from randomized clinical trials to the real-world. A high rate of stent thrombosis, either in the entire registry or in any subgroups, would obviously be an important finding. Similarly, if there’s a low rate of stent thrombosis, which preliminary data from the registries are starting to show, that will be very reassuring. Also, the device is going to be utilized in the registries in more complex lesions and scenarios beyond those that were studied in TAXUS IV. We’ll get some preliminary data regarding efficacy in those subgroups, although registry data can’t take the place of well-designed randomized trials. What sort of approach do you think that cardiologists should be taking with Taxus until the longer-term data becomes available? In general, the risk-benefit ratio must be considered for each individual patient, given the state of our knowledge (or lack thereof). Regarding both Taxus and Cypher, I don’t think I’d treat them any differently in that regard. There are certain types of lesions that represent a natural extension to the studies that have been done already (such as chronic total occlusions), and with favorable registry data starting to come in. Yet there are other lesion subtypes that I think we really have no data on, or data that suggest there still remains issues, such as left main and bifurcation disease, where physicians need to be more circumspect about applying these devices without adequately powered studies. What do we know about drug- eluting stents after failed brachytherapy for in-stent restenosis? We don’t have the final answer for this complex scenario yet. It does seem that after drug-eluting stent implantation for restenosis following failed brachytherapy, there may be a slightly higher incidence of stent thrombosis, and possibly a late catch-up phenomenon in terms of recurrent late restenosis. This observation primarily comes from the SECURE registry study with the Cypher stent. The reason for this finding may be that brachytherapy inhibits endothelialization and so late events can continue to occur, even with a drug-eluting stent. More studies are clearly needed before we can be certain of the safety and efficacy of drug-eluting stents in this setting, either with Taxus or Cypher. Until then, we are trying to avoid the combination of drug-eluting stents and brachytherapy whenever possible. What about either stent’s effectiveness in diabetic patients? Both Taxus and Cypher are effective in diabetics, though we can’t yet definitively say whether one is superior to the other. So far, from both the TAXUS II and TAXUS IV studies, the paclitaxel-eluting Taxus stent appears to be just as effective in both oral and insulin-dependent diabetics as in non-diabetic patients. The outstanding question is whether sirolimus is just as effective in diabetics. Not enough patients have been studied to answer that question yet. There’s a recently completed head-to-head trial of Taxus and Cypher in Europe called the REALITY study. REALITY enrolled 1863 patients with small vessels (2.25 -3.0 mm), more than 30% of whom had diabetes. The results of this study will be very important to provide insight as to the relative efficacy of the two in diabetics. We ought to have that later this year. What are some of the more challenging cases you’ve been doing at your facility? Well, we’re certainly starting to do more unprotected left main cases with drug-eluting stents on a routine basis, in the setting of an FDA approved registry investigation. These would typically go to surgery, but now with the promise of a very low restenosis rate with drug-eluting stents, we’re cautiously entering that sphere. We always have honest and open discussions with the patients, explaining the pros and cons of this approach and emphasizing the lack of data in this area. The treatment of complex, multi-lesion, double and triple vessel disease, often with one or more true bifurcation lesions, is now becoming routine. How important would you say deliverability is when choosing a stent? Stent flexibility and deliverability is extremely important. Obviously a drug-eluting stent can’t work if you can’t get it there. In addition, it’s one thing to get it there, and it’s another thing to get it there easily. The easier you can get a device there, the less likely you are to have procedural complications, the lower the contrast and radiation exposure will be, etc.. For most lesions, I think you can get Cypher and Taxus there without any question. I think that there are a series of lesions the more complex, tortuous, calcified vessels, where the Taxus stent may be more deliverable. Different operators will appreciate the difference in deliverability to different degrees. What are your thoughts on the recent study showing that direct stenting with Cypher can have good outcomes in certain patients? The DIRECT study was released at the American College of Cardiology meeting in March. It was 250 or so patients with lesions that operators felt were amenable to direct stenting. In those patients, the outcomes were excellent with the Cypher stent. It is important to realize that compared to the lesions in the SIRIUS trial, the lesions in the DIRECT study were somewhat shorter. All the data suggest that in appropriately selected lesions, with the Cypher stent, it’s a safe and effective approach, and is associated with at least as good outcomes as pre-dilatation. Comparisons between Cypher and Taxus are ongoing and inevitable. Do you have any guidelines on whether we should take device-specific data and apply it to general thinking about all drug-eluting stents? Should we apply only Cypher data to Cypher, and only Taxus data to Taxus? If you want to prove something about a particular device, the purest point of view holds that you do need to prove it with that device, in a very directed clinical trial. For example, the DIRECT data on direct stenting applies only to the Cypher stent. We don’t have strong evidence yet to suggest that the Taxus stent behaves similarly. We do have a lot of bench data, showing that it’s extraordinarily difficult to remove the polymer from the Taxus stent. From that experience and from anecdotal experience, I expect that direct stenting would be fine with the Taxus stent. But I would prefer if I had a clinical trial showing excellent results to be able to state that definitively. Gregg Stone, MD discloses he has received a research grant from Boston Scientific Corporation.

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Background Notes The following information offers a more in-depth look at some of the trials mentioned by Dr. Stone. Enrollment Concludes in TAXUS V Clinical Trial Boston Scientific has concluded enrollment in its TAXUS V de novo lesion clinical trial. The trial has enrolled 1,172 patients, surpassing the required sample size of 1,108. The U.S. Food and Drug Administration (FDA) confirmed that the Company has reached sufficient enrollment to meet all the required trial analyses, and that it may therefore close enrollment in the trial. The TAXUS V clinical trial expands on the TAXUS IV trial, which established the safety and efficacy of the Taxus Express2 paclitaxel-eluting stent system. TAXUS V is studying a higher-risk patient population than TAXUS IV. Final results are expected in early 2005, when the nine-month follow-up data have been analyzed. The lesions enrolled in TAXUS V are some of the most challenging we face as interventional cardiologists, said Gregg Stone, MD, Principal Investigator of TAXUS V and Director, Cardiovascular Research and Education, The Cardiovascular Research Foundation at the Lenox Hill Heart and Vascular Institute in New York. We are hopeful that the outcomes of TAXUS V in this higher-risk patient population will extend the results from TAXUS IV, broadening the range of patients who may benefit from this breakthrough technology. The TAXUS V ISR (in-stent restenosis) trial is an independent trial evaluating outcomes in patients who have developed narrowing in a bare-metal stent. This trial continues to enroll patients. ARRIVE: Drug-Eluting Stent Registry Examines Real-world Safety and Clinical Outcomes of Taxus Express2 Paclitaxel-eluting Stent System The ARRIVE registry program plans to enroll 2,000 patients at approximately 50 centers in the United States. It is designed to collect and analyze real- world safety and clinical outcomes data for the Taxus Express2 paclitaxel-eluting stent system in the treatment of patients with coronary artery disease. In cooperation with the U.S. Food and Drug Administration (FDA), the ARRIVE registry was initiated prior to FDA approval of the TAXUS system. The registry continues post-approval. The registry’s Co-Principal Investigators are David Cox, MD, of Mid Carolina Cardiology in Charlotte and John Lasala, MD, PhD, of Barnes- Jewish Hospital and Washington University School of Medicine in St. Louis. Dr. Cox enrolled the first patients in the ARRIVE registry beginning in February 2004. The SECURE Trial The SECURE trial enrolled 252 patients treated at 5 U.S. clinical sites. Initiated prior to FDA approval of the sirolimus-eluting stent, compassionate use of the Cypher stent in this registry was indicated for patients with a serious disease or condition for which there were no acceptable treatment alternatives available, including brachytherapy or coronary artery bypass graft surgery. The majority of patients had failed brachytherapy for in-stent restenosis. Multiple stents were allowed and clopidogrel was maintained indefinitely for patients with previous brachytherapy failure. Using data from the SECURE trial, 6-month follow-up data of the first US experience with the use of SES for the treatment of bypass grafts (47 patients, 57 lesions) were presented at the AHA meeting. There was no acute or subacute stent thrombosis after SES implantation in bypass grafts. The 6-month incidence of MACE was 20.1% in patients with at least 1 bypass graft treated as compared with 30% for those treated exclusively for native coronary artery lesions. Another subanalysis of SECURE presented at the AHA meeting showed a higher incidence of target vessel revascularization (TVR) for patients who had experienced previous brachytherapy failure vs patients without previous irradiation (23.4% vs 8.5%, respectively).Given this extremely high-risk patient population (> 60% of patients had previous brachytherapy failure), the outcomes observed in this study were considered favorable. From: Costa M, Lemos P. Registries and Real-World Practice of Drug-Eluting Stents. A CME activity from Medscape Conference Coverage, based on selected sessions at the American Heart Association Scientific Sessions 2003. Available at: https://www.medscape.com/viewprogram/2865

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