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Second-Generation Drug-Eluting Stents and the Continuous Need for Rapidly Available Real-World Data^_*

Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky

Key Words: drug-eluting stents • Endeavor stent • Xience stent • real-world data

The large randomized 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 demonstrated that EES resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events (MACE) than PES during 1-year follow-up (3). Two-year follow-up showed that patients treated with EES had a significantly improved event-free survival compared with PES-treated patients (4). On the basis of favorable data and ease of deliverability, EES quickly became a global market contender and captured more than 50% of the U.S. market (5). The initial enthusiasm regarding ZES was dampened by greater angiographic late-loss compared with other DES as reported in the ENDEAVOR II (Long-Term Clinical and Economic Analysis of the Endeavor Drug-Eluting Stent Versus the Driver Bare Metal Stent: 4-Year Results from the Endeavor Zotarolimus-Eluting Phosphorylcholine-Encapsulated Stent for Treatment of Native Coronary Artery Lesions Trial) (6) and ENDEAVOR IV (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) (7) trials, although this did not translate into a higher early rate of TVR. Gershlick et al. (8) pooled outcomes from the first several ZES clinical studies including 1,317 patients and reported that, despite varied baseline clinical and angiographic characteristics, treatment with the ZES was associated with consistently low rates of TVR, stent thrombosis, and overall MACE at 2-year follow-up.

Clinical outcome data from everyday practice were very limited for both EES and ZES until recently. Before the present publication by Latib et al. (9), data considering the effectiveness of EES for complex lesions among unselected patients were only available from the X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) registry (10). The X-SEARCH registry included 649 consecutive patients who were treated exclusively with EES and compared with historical control subjects. The results suggested that EES have safety similar to BMS and both first-generation DES, are more effective than BMS and PES, and are similarly effective as SES. In this issue of JACC: Cardiovascular Interventions, Latib et al. (9) report unrestricted EES implantation in an observational study of 345 patients. The EES were implanted predominantly for off-label indications (72%) and were associated with a relatively low rate of MACE (11%) and target lesion revascularization (8%) at a median follow-up of 1 year. This study provides clinically relevant data on the usefulness of EES in practice but has limitations, given its relatively small cohort size and single-center experience. Another paper in this issue of JACC: Cardiovascular Interventions provides large-scale perspective on the performance of ZES in real-world settings with the E-Five registry (A World-Wide Registry With The Endeavor Zotarolimus Eluting Coronary Stent) as reported by Lotan et al. (11). The E-Five registry is a prospective, nonrandomized, global registry including 188 centers and 8,314 patients undergoing percutaneous revascularization with ZES. The 12-month MACE rates were 4.3% and 8.6% for standard-use and extended-use patients, respectively (p < 0.001), suggesting a doubling of event rates for off-label or extended use of ZES as compared with standard use (11).

Given that most interventionalists now have at least 4 types of DES available, the important question to be asked is: "What should clinicians realistically expect in terms of outcomes if second-generation DES were to be implanted in unselected patients including those with complex coronary lesions?" The reports by Latib et al. (9) and Lotan et al. (11) alone cannot completely answer this question but do add important perspective. As noted, MACE rates were almost double among patients with off-label use of EES or ZES compared with on-label use, although the differences did not reach statistical significance in the Latib et al. (9) study. Also the TVR rates were roughly 50% to 80% higher with off-label use. As such, the overall message to interventionalists from these 2 reports should be that the EES and ZES are safe and effective when used for on-label indications, and somewhat higher event rates should be anticipated when they are used in more complex lesion subsets.

Larger datasets are needed from multicenter post-marketing studies to define the magnitude of the increase in event rates with more widespread DES use and also to ascertain how second-generation DES perform relative to both of the first-generation DES regarding TVR. The FDA recommended to the manufacturers of DES that post-approval studies not be used to evaluate important unresolved safety and effectiveness issues from the premarket phase. Instead, post-approval studies should: 1) assess whether stent thrombosis rates plateau or continue to increase over time; 2) assess the incidence rate of cardiac death and myocardial infarction (MI); 3) gather information on antiplatelet therapy use; and 4) study routine clinical use of DES (12,13). Such delineation of outcomes in unselected patients will eventually come from several ongoing multicenter registries evaluating second-generation DES (Table 1).

This issue of JACC: Cardiovascular Interventions also includes long-term clinical and economic analysis of the ZES from several ENDEAVOR trials, including ENDEAVOR II (18), III (19), and IV (20). The common message from these analyses is that ZES demonstrates comparable clinical efficacy and economic attractiveness to first-generation DES with improved safety (fewer occurrences of MI and very late stent thrombosis). Again, the higher initial angiographic late-loss with ZES did not translate into subsequent higher TVR rates in these studies. Together, this has the potential to make ZES an attractive option compared with first-generation DES by providing lower or comparable medical costs and better safety and quality-adjusted survival. However, not all studies to date have reported similar safety and efficacy profiles for ZES when compared with first-generation DES. The SORT-OUT III (A Prospective Randomized Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Stents in Patients with Coronary Artery Disease) trial reported significantly higher stent thrombosis, MI, and target lesion revascularization rates with ZES than SES (21). Separately, the ZEST (Zotarolimus-Eluting Stent Versus Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions) trial compared ZES, SES, and PES and found no differences in death or in MI at 1-year follow-up (22).

With these varied reports it seems intuitive that future trials and prospective registries assessing next-generation DES will need to be quite large to adequately answer questions regarding safety (primarily stent thrombosis) and efficacy (primarily in reducing TVR), especially considering the growing category of "extended use." At the same time other factors known to affect outcome (e.g., potency and duration of dual antiplatelet therapy) need to be prospectively defined and controlled as best possible. In summary, despite an initial lack of data from complex patient subsets receiving second-generation DES, there are now substantial reassuring data, and new benchmarks are being set. In the future, it should be a goal to obtain and report clinical-experience data more rapidly so that, as new-generation devices emerge, outcome provided by their predecessors will already be established and well-understood. New device discovery and development should not slow, but rather the accumulation, interpretation, and dissemination of our collective real-world experience need to accelerate and be more systematic.

	Footnotes

 
Dr. Moliterno has received past honoraria for serving on the Data and Safety Monitoring Committees for Boston Scientific and Guidant/Abbott, manufacturers of drug-eluting stents.

^_* 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.

^_* Reprint requests and correspondence: Dr. Debabrata Mukherjee, Division of Cardiovascular Medicine, University of Kentucky, 900 South Limestone Street, 326 Wethington Building, Lexington, Kentucky 40536-0200 (Email: Mukherjee{at}uky.edu).

	REFERENCES

Top REFERENCES

 

1. 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.[Abstract/Free Full Text]
2. Kandzari DE, Leon MB, Popma JJ, et al. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial J Am Coll Cardiol 2006;48:2440-2447.[Abstract/Free Full Text]
3. Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial JAMA 2008;299:1903-1913.[Abstract/Free Full Text]
4. Stone GW, Midei M, Newman W, et al. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial Circulation 2009;119:680-686.[Abstract/Free Full Text]
5. Goldstein J. Abbott Looks Like the New Stent King Wall Street Journal. 2008.
6. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial Circulation 2006;114:798-806.[Abstract/Free Full Text]
7. Waseda K, Miyazawa A, Ako J, et al. Intravascular ultrasound results from the ENDEAVOR IV trial: randomized comparison between zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease J Am Coll Cardiol Intv 2009;2:779-784.[Abstract/Free Full Text]
8. Gershlick A, Kandzari DE, Leon MB, et al. Zotarolimus-eluting stents in patients with native coronary artery disease: clinical and angiographic outcomes in 1,317 patients Am J Cardiol 2007;100:45M-55M.[Web of Science][Medline]
9. Latib A, Ferri L, Ielasi A, et al. Clinical outcomes following unrestricted implantation of everolimus-eluting stents J Am Coll Cardiol Intv 2009;2:1219-1226.[Abstract/Free Full Text]
10. Onuma Y, Kukreja N, Piazza N, et al. The everolimus-eluting stent in real-world patients: 6-month follow-up of the X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) registry J Am Coll Cardiol 2009;54:269-276.[Abstract/Free Full Text]
11. Lotan C, Meredith IT, Mauri L, Liu M, Rothman MT, E-Five Investigators Safety and effectiveness of the Endeavor zotarolimus-eluting stent in real-world clinical practice: 12-month data from the E-Five registry J Am Coll Cardiol Intv 2009;2:1227-1235.[Abstract/Free Full Text]
12. Duggirala H. Abbott Xience Post-Approval Considerations. XIENCE V Everolimus Eluting Coronary Stent System FDA Review Committee. Gaithersburg, MD: Food and Drug Administration; 2007.
13. Torguson R, Waksman R. Overview of the 2007 Food and Drug Administration Circulatory System Devices Panel meeting on the Xience V Everolimus-Eluting Coronary Stent Am J Cardiol 2008;102:1624-1630.[CrossRef][Web of Science][Medline]
14. Grube E. SPIRIT V Registry 1 Year Follow-up. Paper presented at: EuroPCR 2009; Barcelona, Spain.
15. Stone GW. SPIRIT IV TrialPaper presented at: Transcatheter Cardiovascular Therapeutics (TCT); San Francisco, CA 2009.
16. Smits P. COMPARE TrialPaper presented at: Transcatheter Cardiovascular Therapeutics (TCT); San Francisco, CA 2009.
17. Garg S, Serruys PW, Onuma Y, et al. SPIRIT II Investigators 3-year clinical follow-up of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions: the SPIRIT II trial (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) J Am Coll Cardiol Intv 2009;2:1190-1198.[Abstract/Free Full Text]
18. Eisenstein EL, Wijns W, Fajadert J, et al. Long-term clinical and economic analysis of the Endeavor drug-eluting stent versus the Driver bare metal stent: 4-year results from the ENDEAVOR III trial (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions) J Am Coll Cardiol Intv 2009;2:1178-1187.[Abstract/Free Full Text]
19. Eisenstein EL, Leon MB, Kandzari DE, et al. ENDEAVOR III Investigators Long-term clinical and economic analysis of the Endeavor zotarolimus-eluting stent versus the Cypher sirolimus-eluting stent: 3-year results from the ENDEAVOR III trial (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) J Am Coll Cardiol Intv 2009;2:1199-1207.[Abstract/Free Full Text]
20. Leon MB, Kandzari DE, Eisenstein EL, et al. ENDEAVOR IV Investigators Late safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent compared with a paclitaxel-eluting stent in patients with de novo coronary lesions: 2-year follow-up from the ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) J Am Coll Cardiol Intv 2009;2:1208-1218.[Abstract/Free Full Text]
21. Lassen JF, Rasmussen K, Galloe A, et al. SORT-OUT III: A Prospective Randomized Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Stents in Patients with Coronary Artery DiseasePaper presented at: Transcatheter Cardiovascular Therapeutics; Washington, DC 2008.
22. Parks S. Major clinical endpoints in ZEST at one yearPaper presented at: American College of Cardiology; Orlando, FL 2009.

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