RAVEL
Dr. Fajadet presented the 7-month angiographic follow-up and 1-year clinical follow-up from the Randomized Study with the Sirolimus-Eluting Bx-Velocity Balloon Expandable Stent in Patients with De Novo Native Coronary Artery Lesions ( RAVEL) study, a randomized, double-blind controlled study of the safety and efficacy of the sirolimus (Rapamycin) eluting Bx-Velocity stent (Cordis). This study included 19 centers (15 in Europe and 4 in Latin America) that enrolled 238 patients with stable angina, unstable angina or silent ischemia. All had de novo lesions with > 50% diameter stenosis in a coronary artery between 2.5 and 3.5 mm in diameter, that could be treated with a single stent 18 mm in length and had no contraindication to thienopyridine administration. Patients were randomized to receive an unmedicated control stent (n = 118) or a sirolimus-eluting coated stent (n = 120). All patients were treated with clopidogrel for 2 months after stent implantation. The primary end point of the study was angiographic late loss within the stented segment at 6 months as assessed by quantitative coronary angiography (QCA). Secondary angiographic end points included angiographic restenosis (> 50% diameter stenosis) and per cent diameter stenosis. The 6-month angiographic data from this trial had been previously presented at the European Society of Cardiology Meeting in September 2001. The clinical outcomes including target vessel revascularization (TVR) and target lesion revascularization (TLR), and major adverse cardiac events (MACE) at 6 months and 1 year were reported at this meeting. In addition, data from subgroup of 94 patients evaluated using intravascular ultrasound (IVUS) at 6 months were presented.
The baseline clinical and angiographic characteristics of the two groups were briefly outlined. There were no significant differences between the groups receiving the sirolimus coated vs. control stents with respect to percentage of diabetics (16% vs 21%), presentation with an acute coronary syndrome (48% vs 50%), baseline reference vessel diameter (2.6 mm vs 2.64 mm), lesion length (9.6 mm for both groups) or post procedural minimal lumen diameter (2.43 mm vs 2.42 mm). Glycoprotein IIb-IIIa use was low and equivalent between the two groups (approximately 10%).
For the primary end point at 6 months, QCA revealed that intrastent late loss was significantly less (and almost nonexistent) in the patients who received a sirolimus coated stent when compared to patients who received control stents (-0.01 ± 0.33 mm vs 0.8 ± 0.53 mm; P < 0.0001). Follow-up minimal lumen diameters were 2.32 mm and 1.56 mm respectively (P < 0.0001). This resulted in 6-month angiographic restenosis (binary definition, > 50% diameter stenosis) rates of 0% in the sirolimus group and 26% in the control group (P < 0.0001). Dr. Fajadet reported that the effect of sirolimus was consistent across all terciles of vessel size, suggesting that the coated stents were equally effective in the smaller-caliber vessels. In the small diabetic subpopulation (19 patients receiving sirolimus stents and 25 receiving control stents), there was significant inhibition of late loss and no angiographic restenosis in patients who received sirolimus coated stents. QCA analysis showed equivalent prevention in the sirolimus group of late loss at the proximal edge, within the body of the stented segment and at the distal edge, suggesting that there was no angiographic evidence of an edge effect at the ends of the implanted stents. The IVUS substudy showed significantly larger lumen volumes (129 mm3 vs 95 mm3; P < 0.0001) and significantly smaller neointimal volumes (37 mm3 vs 2 mm3; P < 0.0001) in patients receiving the sirolimus coated stents at 6 months. Dr. Fajadet briefly mentioned in his discussion that approximately 20% of sirolimus stents vs. 4% of control stents were judged to show some evidence of incomplete apposition (a single strut not adjacent to the vessel wall). However, this did not appear to be due to a positive remodeling effect as the external elastic lamina (EEL) areas were equivalent between the 2 groups.
Clinical outcomes at 6 and 12 months were also better in the patients treated with sirolimus coated stents. At 6 months, 1 patient in each group received TVR by coronary artery bypass grafting. There were no TLR events in the sirolimus group out to 12 months, compared with 26 (22%) at 6 months and 27 (22.9%) at 12 months in the group receiving the control stents. Survival free of MACE (death, MI, or repeat PCI) at 1 year was 94.2% in the sirolimus group and 71.2% in the control group. There were 2 deaths in each group. Deaths in the patients receiving sirolimus coated stents were attributed to gastrointestinal malignancy and subarachnoid hemorrhage. There were no events attributed to subacute or late stent thrombosis in either group.
Dr. Fajadet summarized by saying that the patient receiving sirolimus coated stents experienced no subacute thrombosis, no late thrombosis, no restenosis, no edge effect and out to one year, no evidence of "catch up" in clinical event rates.
Comment by Sarah M. Vernon, MD
"Coated" or drug-eluting coronary stents were described as the "media darling" of the first day of ACC 2002, as well they should have been. The 1-year follow-up of RAVEL seems to be another nail in the coffin for in-stent restenosis. This is a particularly important trial, not only because of what appears to be a powerful effect of this preparation of sirolimus on neointimal proliferation, but also because this is one of few truly double-blinded trials in interventional cardiology (the appearance of the coated stent is indistinguishable from the control). Additional clinical information about this stent is available and more is forthcoming. Follow up from the small, initial experience with the sirolimus eluting Bx-Velocity stent from Sousa and colleagues,1 now referred to as the "First-in-Man" study followed later in the session. At 2 years of follow-up, this uncontrolled series of 45 patients using slow-release (as in RAVEL) and fast-release dose delivery systems, also treated with 60 days of clopidogrel continues to show essentially no angiographic late loss (-0.09 mm) and reports no adverse events such as late thrombosis or aneurysm formation. In addition, more information will come from SIRIUS, a large, US based, randomized trial evaluating this same stent, which has completed enrollment of more than 1000 patients is now in the angiographic phase of follow-up. Several other drug, coating and stent combinations are also being tested in ongoing clinical trials, and data from these will be following close on the heels of the sirolimus eluting Bx-Velocity. However, the latter is likely to be approved for clinical use in Europe soon and will undoubtedly be the first FDA-approved coated stent available for use in the United States.
In all of the enthusiasm, it is important not to ignore the science. There is still a lot we don’t know about "coated stents." Many questions remain as to what will prove to be the best therapy the stent "delivery system" has to offer. It will probably be a long time before we know if sirolimus is better than paclitaxel or tacrolimus or actinomycin-B. Many questions about dose, dose-density and rate/duration of release are yet unanswered. A variety of coatings used to attach the drug to the stent and deliver it locally are currently under investigation. Many questions remain about the potential for late adverse effects such as aneurysm formation, or late proliferative effects, or, as one investigator put it, the possibility of "creating some entirely new disease process that didn’t even exist before." In the absence of good animal models, the answers to many of these questions won’t be known until long after many of these devices have been implanted in patients.
We have endured many years of innumerable investigations of a plethora of potential anti-restenosis agents, many of which held great theoretical promise based on our understanding of the vascular biology of the process. Stenting has made a significant effect, but is still limited in many clinical scenarios, such as small vessels, and has created in its wake another more difficult problem: in-stent restenosis (ISR). Until recently, the only approach to this disease process has been prevention, by adequate deployment technique, lesion selection and luck. Intravascular brachytherapy has proven to be effective in the treatment of ISR, but not in every case, and not without the specter of (somewhat unanticipated) late thrombotic events. More importantly, the availability of brachytherapy has probably been limited due to its logistical issues: the need for participation of a radiation oncologist and a radiation physicist make this technology difficult to deliver in many, if not most, catheterization laboratory settings. Implanting a coated stent is exactly like implanting the stents we all deal with on a daily basis. The technology is familiar and accessible. So easy, in fact, that if the promise holds true, some operators are envisioning a day when the noncritical, but vulnerable plaque might be prophylactically "sealed" to prevent it from rupturing in the future (Now that’s what I call preventive cardiology!). It is easy to see why these devices hold so much appeal for interventional cardiologists, patients, and Wall Street investors alike. (In fact, many of our patients already specifically request to have a coated stent placed!) With a projected price tag of $3500, the real hurdle will be finding a way to pay for them.
Reference
1. Sousa JE, et al. Circulation. 2001;103:192-195.
Dr. Vernon is Assistant Professor of Medicine, Director , VAMC Cardiac Catheterization Laboratory, University of New Mexico, Health Sciences Center, Albuquerque, NM.
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