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- James R. Margolis, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. James R. Margolis, Miami International Cardiology Consultants, 3801 Biscayne Boulevard, Miami, Florida 33137
In their report of the CREATE (Multi-Center Registry of Excel Biodegradeable Polymer Drug-Eluting Stents) study in this issue of JACC: Cardiovascular Interventions, Han et al. (1) suggest that the Excel stent (JW Medical System, Weihai, China)—a sirolimus-eluting stent with biodegradable polymer—has equal or superior major adverse cardiac event (MACE) rates to presently available drug-eluting stents (DES). Because the biodegradable polymer precludes late stent thrombosis (LST), only 6 months of clopidogrel are required. This is a well-designed study performed in a scientific manner. The data are reported objectively, and the authors recognize the deficiencies of a registry. Upon first reading, the results are impressive. On closer inspection, it is necessary to ask what the study actually showed, and is there any solid evidence that Excel is superior to presently available DES?
The authors conclude that the outcomes of the present study demonstrate:
• Satisfactory efficacy and safety profiles for the Excel biodegradable polymer-based sirolimus-eluting stent in treating patients in “real-world” settings, with low rates of MACE and stent thrombosis up to 18 months.
• The outcomes also suggest that 6 months of dual antiplatelet therapy with clopidogrel and aspirin after Excel stent implantation is safe and feasible.
Although I agree with the first conclusion, I do not believe that the data support the conclusion that it is safe to stop clopidogrel and aspirin 6 months after Excel stent implantation.
The Excel Stent
The Excel stent has a sirolimus coating bound to an S-Stent (Biosensors International, Singapore). The S-Stent is a stainless steel stent that is said to provide superior deliverability in small and tortuous vessels. The unusually low early MACE rate in this study suggests that this claim may be true. The biodegradable polymer is polylactic acid. The coating can be expected to degrade fully in 6 to 9 months. The authors hypothesize that degradation of the polymer coating will decrease inflammation around the stent, thereby reducing late hypersensitivity and decreasing the risk of in-stent thrombosis. There are limited clinical or even animal data to support this hypothesis. These include 1 well-documented case report of death due to LST with a prolific eosinophilic reaction (2), and a recent report of 4 possible cases derived from reports of adverse events in Food and Drug Administration databases (3).
LST in DES
The problem of LST with DES is a real one, and its importance cannot be overemphasized. The occurrence is well documented (4–6). The causes are generally understood (7). Although the incidence is low, and possibly no different than with bare-metal stents (6), LST with DES frequently results in major myocardial infarction or death (4).
LST with DES has been correlated with incomplete stent endothelialization, and stent underexpansion (7). Long-term clopidogrel appears to reduce the problem, but this has not been demonstrated in prospective studies. Because LST in DES can occur even several years after stent implantation, there is no universal agreement as to how long clopidogrel administration is necessary.
The idea that LST is related to the polymer coating used to bind drug in DES is attractive but entirely unproven. The underlying problem seems to be incomplete healing with continuing exposure of metallic stent surfaces (7). Incomplete healing may persist for years, especially if small amounts of residual drug remain. Biodegradable polymer coating might mitigate this problem by assuring the disappearance of residual drug, but this is also unproven.
Results of the CREATE Study and Comparison With Other Studies
Cumulative MACE rates in the CREATE study were 0.9% at 30 days, 2.7% at 1 year, and 3.7% at 18 months. MACE beyond 30 days was 1.8% at 1 year and 2.8% at 18 months. These data compare favorably with those from comparable studies: the SIRIUS (Sirolimus-Eluting Stent in Coronary Lesions) study 9-month MACE 7.3% (8); the TAXUS IV study 12-month MACE 10.8% (9); the SYNTAX (The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) study 12-month MACE 17.8% (10).
Much of the advantage in the CREATE registry is accounted for by the very low initial MACE rates: 0.9% 30 days versus 2.4% in the SIRIUS study (8), 2.5% in the TAXUS IV study (9), and 4% in the SYNTAX study (10). Even taking the above into account, there still appears to be an advantage for Excel in comparison with Cypher and Taxus: Excel 30 days to 1 year MACE 1.8%; Cypher 30 days to 9 months 5.1% (8); Taxus 30 days to 12 months 8.3% (9).
The low early MACE rates in the CREATE study may be explained by a number of factors:
1. Lesion and clinical characteristics
2. Skill of the investigators
3. Under-reporting of events
4. Differences between registries and randomized studies
5. Favorable characteristics of the S-Stent and its delivery system
With the available data there is no way to judge the role of #1, #2, and #3. Data from previous Cypher registries speak to #4. The 30-day MACE rate for Cypher was 2.4% in the U.S. SIRIUS trial (8), but only 1.0% in a post-market surveillance study (11).
The favorable deliverability of the S-Stent is the most likely explanation for low MACE rates in the CREATE registry. Similarly low MACE rates were seen in studies of Xience V (30-day MACE 1.5% in the Spirit III [Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de novo Native Coronary Artery Lesions] study ) (Abbott Vascular, Abbot Park, Illinois) and Endeavor (30-day MACE 1.2% in the Endeavor IV [Randomized Comparison of Zotarolimus-Eluting and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease] study ) (Medtronic, Inc., Minneapolis, Minnesota)—2 DES whose deliverability are superior to that of Cypher and TAXUS.
Although it is difficult to compare registry studies to randomized studies, the CREATE data suggest an advantage for the Excel stent. In the population studied, and in the hands of the CREATE study investigators, the initial MACE rates are incredibly low—not only in comparison with other DES studies, but also compared with studies comparing stenting to medical or surgical management (e.g., 30-day MACE for the COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation] study 2.5% , the SYNTAX study 4% ).
With the effectiveness of most DES in reducing target lesion revascularization to extremely low levels, initial MACE rates are increasingly relevant. This is especially true in multivessel stenting, where MACE rates are directly proportional to the number of vessels stented (10). The ability of second generation DES to reduce early MACE through improved deliverability may be more important than any subtle differences in drug effect.
What Can We Say About the Excel Stent?
If the CREATE data are reproducible, the Excel stent has a very low initial MACE rate, presumably due to its excellent deliverability, and it has a target lesion revascularization rate comparable to or better than other DES. The study is too small and the follow-up too short to make a meaningful comment in regard to LST after only 6 months of clopidogrel—especially in light of the fact that 1 LST occurred only 4 days after clopidogrel discontinuation.
Whether or not the biodegradable polymer coating is effective in promoting late healing is not addressed in this study, since there was no evaluation of these patients with either intravascular ultrasound or optical coherence tomography.
↵⁎ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
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