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SPIRIT IV: New evidence that everolimus (XIENCE V®) drug eluting stent (DES) is superior to other DES at least in some patient groups, but questions remain.

Paul Dobesh, Pharm.D.
November, 2010

The introduction of intracoronary bare metal stents (BMS) in the mid 1990s drastically changed the world of interventional cardiology. The use of BMS significantly reduced restenosis rates down to about 20-30% of patients at 6 months compared to as high as 50% with balloon angioplasty. Drug-eluting stents (DES) were introduced in 2002, and were able to reduce the rate of restenosis to approximately 10% by using technology to apply antiproliferative agents at the site of arterial injury.

Despite the benefits in reducing restenosis demonstrated by the use of stents, the disadvantage is the risk of stent thrombosis due to exposed stent struts to circulating blood. Patients are considered to be at risk of developing stent thrombosis until a thin layer of endothelial tissue can grow around the stent struts and prevent the exposure of the stent to the circulation. This process is called re-endothelialization and typically occurs within 2-4 weeks after BMS deployment. Due to the use of antiproliferative agents added to DES, the duration of time needed for re-endothelialization is not well defined and can take up to a year or more.

The initial first-generation DES included stents that released sirolimus (Cypher® stent) or paclitaxel (TAXUS® stent). While there are some differences in the stent platform and release kinetics between these DES, there has not been a clear differentiation as far as efficacy and safety. The newly approved second-generation everolimus DES (XIENCE V® stent) has recently been compared in a head-to-head trial to the paclitaxel DES in the SPIRIT IV trial1.

Patients (n=3687) were randomized in a single-blinded fashion to receive a everolimus DES or a paclitaxel DES for stable or unstable coronary artery disease.1 The primary endpoint of the trial was the composite rate of target-lesion failure, which was made up of cardiac death, target-vessel myocardial infarction (MI), or ischemia-driven target-lesion revascularization (TLR). After one year of follow up, there was a significant 38% relative reduction (absolute reduction of 2.6%) in the primary endpoint with the everolimus DES (4.2%) compared to the paclitaxel DES (6.8%; p=0.001). The everolimus DES provided a significant reduction in ischemia-driven TLR (2.5% vs. 4.6%; p0.001), MI (1.9% vs. 3.1%; p=0.02) and stent thrombosis (0.17% vs. 0.85%; p=0.004), with no difference in mortality. The benefits of the everolimus DES were consistent across several subgroups except for patient with diabetes mellitus, in which the results between the DES were similar.

These results are consistent with a large single-center trial (n=1797) published early this year called the COMPARE trial.2 The primary endpoint of the COMPARE trial was slightly different than the SPIRIT IV trial in that it was a composite of all cause mortality, MI, and target vessel revascularization. After the year of follow-up there was a significant 31% relative reduction (3% absolute reduction) in the primary endpoint with the use of the everolimus DES (6%) compared to the paclitaxel DES (9%; p=0.02). Once again, there were significant reductions in the rate of target vessel revascularization, MI, and stent thrombosis. The results in patients with diabetes mellitus were similar to the SPIRIT IV trial, in which there were similar outcomes between the two DES.

The results of these trials raise a number of important questions. The first question may be, what is it about the everolimus DES that would allow it to perform better than the paclitaxel DES? It is important to consider that there are three main components to any DES: the drug, the polymer, and the stent platform. Everolimus is an analog of sirolimus and has the same mechanism of action. While this class of agents may be better antiproliferative agents compared to paclitaxel, this remains unproven and controversial. The difference in drugs is unlikely to explain the differences in outcomes seen in the SPIRIT IV and COMPARE trials, since these dramatic differences have not been demonstrated in DES trials comparing sirolimus and paclitaxel.

The main difference between the two DES is in the stent platform and the amount of polymer coating. The everolimus DES uses a flexible cobalt-chromium stent platform compared to the stainless steel platform of the paclitaxel DES. The difference in stent platform material allows the everolimus DES to have stent struts that are almost 40% thinner than that of the paclitaxel DES (81 µm vs. 131 µm).3 The difference also allows for a 60% thinner coating on each stent strut (7.8 µm vs. 19.6 µm).3 The thinner struts and thinner coating may allow for better stent apposition upon deployment in coronary vessel and also more consistent release of drug. Another major advantage of using a DES with thinner struts is that they require less endothelialization to completely cover the stent struts. Data using rabbit iliac arteries nicely demonstrate a correlation between the thickness of stent struts and the delay in re-endothelialization.4 While all patients in the SPIRIT IV and COMPARE trials received a year of aspirin and clopidogrel, the use of a shorter duration of dual antiplatelet therapy may warrant study in patients receiving an everolimus DES for the prevention of stent thrombosis.

Another question from these data is the lack of difference in outcomes in patients with diabetes mellitus. It may be that the mechanism of restenosis in patients with diabetes mellitus is different compared to patients without diabetes, and that other antiproliferative agents may need to be used in these patients.5 This is an important question since approximately 30% of patients with coronary artery disease also have diabetes mellitus.

So is there now a "best" DES and are the first-generation DES going away? Not completely. A couple of things need to be considered. First, the SPIRIT IV trial did not evaluate patients receiving a DES for treatment of MI. Most of the procedures in this trial were on lower to moderate risk patients, and therefore, the outcomes with these two DES in patients presenting with MI is unknown. Another issue to consider is one of cost. Currently the everolimus DES is about $300 more per stent compared to either of the first-generation DES. Therefore, if it is cost effective, everolimus DES should be used instead of a paclitaxel DES in patients without diabetes mellitus for treatment of stable and unstable angina. Patient with diabetes mellitus could be treated with either stent, but based on the cost difference, it would seem prudent to use the less costly DES. In fact, a sirolimus DES may be preferred in patients with diabetes mellitus as some data, but not all, suggest better outcomes compared to a paclitaxel DES.6-8 While there is no reason to believe that the outcomes in patients with MI would be dramatically different, the study comparing these DES will be needed before recommendations can be made. So for now, there is a "better" DES for some patients, but not all, not yet.

References:

  1. Stone GW, Rizvi A, Newman W, et al for the SPIRT IV Investigators. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663-1674.
  2. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet 2010;375:201-209.
  3. Doostzadeh J, Clark LN, Bezenek S, Pierson W, Sood PR, Sudhir K. Recent progress in percutaneous coronary intervention: evolution of the drug-eluting stents, focus on the XIENCE V drug-eluting stent. Coron Artery Dis 2010;21:46-56.
  4. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol 2008;52:333-342.
  5. Rocic P. Differential phosphoinositide 3-kinase signaling: implications for PTCA? Am J Physiol Heart Circ Physiol 2009;297:H1970-H1971.
  6. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653-662.
  7. Dibra A, Kastrati A, Mehilli J, et al for the ISAR-DIABETES Study Investigators. Paclitaxel-eluting or sirolimus-eluting stents to prevent restentosis in diabetic patients. N Engl J Med 2005;353:663-670.
  8. Zhang F, Dong L, Ge J. Meta-analysis of five randomized clinical trails comparing sirolimus- versus paclitaxel-eluting stents in patients with diabetes mellitus. Am J Cardiol 2010;105:64-68.
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