Email updates

Keep up to date with the latest news and content from BMC Cardiovascular Disorders and BioMed Central.

Open Access Research article

Clinical outcomes after treatment of multiple lesions with zotarolimus-eluting versus sirolimus-eluting coronary stents (a SORT OUT III substudy)

Troels Thim17*, Michael Maeng1, Jens Flensted Lassen1, Anne Kaltoft1, Lisette Okkels Jensen2, Jan Ravkilde3, Per Thayssen2, Søren Galatius4, Evald Høj Christiansen1, Thomas Engstrøm5, Morten Madsen6, Leif Thuesen1 and Hans Henrik Tilsted3

Author Affiliations

1 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

2 Department of Cardiology, Odense University Hospital, Odense, Denmark

3 Department of Cardiology, Aarhus University Hospital Aalborg, Aalborg, Denmark

4 Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark

5 Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

6 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

7 Department of Cardiology, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark

For all author emails, please log on.

BMC Cardiovascular Disorders 2012, 12:18  doi:10.1186/1471-2261-12-18

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2261/12/18


Received:20 November 2011
Accepted:19 March 2012
Published:19 March 2012

© 2012 Thim et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Data on clinical outcomes among patients treated with the zotarolimus-eluting Endeavor™ stent versus the sirolimus-eluting Cypher™ stent favor the sirolimus-eluting stent. However, a separate comparison of clinical outcome among patients treated for multiple lesions with these stents is lacking. We performed this comparison within the SORT OUT III trial data set.

Methods

Among 2332 patients randomized in SORT OUT III, 695 were treated for multiple lesions with zotarolimus-eluting (n = 350) or sirolimus-eluting (n = 345) stents and followed for 18 months. Major adverse cardiac events (MACE); composite of cardiac death, myocardial infarction, or target vessel revascularization (TVR); was the primary endpoint.

Results

Zotarolimus-eluting compared to sirolimus-eluting stent treatment was associated with increased MACE rate (13.2% vs. 2.6%; hazard ratio 5.29 with 95% confidence interval: 2.59-10.8). All secondary endpoints; all cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization, in-stent restenosis, and definite stent thrombosis; were observed more frequently among zotarolimus-eluting stent treated patients. For all endpoints, hazard ratios were 1.6 to 4.6 times higher than in the overall results of the SORT OUT III trial.

Conclusions

We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent.

Background

Percutaneous coronary intervention (PCI) with drug eluting stent (DES) implantation in single coronary artery lesions has become mainstay [1]. Gradually, PCI with DES of multiple coronary artery lesions, concomitantly, has increased, and PCI of multiple lesions in patients with multivessel disease is under evaluation as an alternative or supplement to coronary artery bypass surgery [2].

In some stent trials with comparison of zotarolimus-eluting and sirolimus-eluting stents, however, stent safety and efficacy have only been evaluated in patients with single lesions [3]. In other trials and registry studies, patients with single and multiple lesions have been analyzed together [4-6]. Trials comparing the zotarolimus-eluting Endeavor™ stent and the sirolimus-eluting Cypher™ stent generally favor the sirolimus-eluting stent [7]. However, a separate analysis of data on patients treated for multiple lesions has not been reported. Considering the current use of DES to treat multiple lesions concomitantly, such a separate analysis is relevant. In the SORT OUT III trial, we compared clinical outcome among all-comers randomized to the zotarolimus-eluting Endeavor™ stent and the sirolimus-eluting Cypher™ stent [5]. In this trial, patients with multiple lesions were included. Here, we make a separate comparison of clinical outcomes among patients treated for multiple lesions with zotarolimus-eluting and sirolimus-eluting stents in the SORT OUT III trial.

Methods

This study was approved by the local ethics committee and complied with the Declaration of Helsinki. Patients provided written, informed consent before participation. The SORT OUT III trial was registered with ClinicalTrials.gov (NCT00660478).

In the framework of the SORT OUT organization, we undertook the SORT OUT III trial; a multi-centre, open-label, randomized, all-comer trial from January 2006 through August 2007 in five Danish high-volume PCI centers [5]. We included patients 18 years or older undergoing PCI. Patients were eligible when they needed DES stent treatment of at least one coronary lesion. There were no upper limits on the number of treated lesions, treated vessels, or lesion length. When more than one lesion required treatment, the allocated study stent should be used to treat all lesions. Exclusion criteria were: inability to provide informed consent; life expectancy of less than one year; allergy to acetylsalicylic acid, clopidogrel, ticlopidine, sirolimus, or zotarolimus; or participation in another randomised trial. Concurrent diseases or advanced age did not preclude participation.

In this substudy, we analyzed clinical outcomes among patients undergoing PCI for multiple lesions (more than one) at the index PCI. When PCI of more than one lesion was needed, non-allocated DES or bare metal stents were only implanted if the allocated study stent could not be implanted.

At the time of the index PCI, we recorded cardiovascular risk factors and comorbidity and calculated Charlson comorbidity score [8,9].

Using a telephone allocation service, we randomized patients after diagnostic coronary angiography and before PCI. With block randomization according to center, patients were randomized 1:1 to receive either the zotarolimus-eluting (Endeavor, Medtronic, Santa Rosa, CA) or the sirolimus-eluting (Cypher Select or Cypher Select+; Cordis, Johnson & Johnson, Warren, NJ) stent. Patients were stratified by gender and the presence or absence of diabetes. Patients were pre-treated with at least 75 mg acetylsalicylic acid, a 300-600 mg loading dose of clopidogrel, and 5,000 IU or 70-100 IU/kg unfractionated heparin. After PCI, dual antiplatelet regimens with lifelong acetylsalicylic acid, 75 mg daily, and clopidogrel, 75 mg daily, for one year, was recommended in accordance with Danish guidelines [10].

Clinical outcomes were assessed at 18 months. The primary endpoint was major adverse cardiac events (MACE) defined as a composite endpoint of cardiac death, myocardial infarction, and target vessel revascularization (TVR). Other endpoints were all-cause death, cardiac death, myocardial infarction, TVR, target lesion revascularization (TLR) (within the stent + 5 mm in proximal and distal directions), symptom-driven observation of in-stent restenosis (within the stent + 5 mm in proximal and distal directions), and definite stent thrombosis. These endpoints have been described previously [5].

Data on mortalilty (cardiac and non-cardiac), hospital admissions, coronary angiography, repeat PCI, and coronary bypass surgery were obtained from national Danish registries (Danish Civil Registration System, National Registry of Causes of Death, Danish National Registry of Patients, the local heart registries in the five PCI centers, and the Danish Heart Register) [11-17]. These cover the entire Danish population.

Independent study monitors, blinded to treatment assignment, reviewed all repeat coronary examinations and interventions (coronary angiography, coronary balloon angioplasty, coronary stent implantation, and coronary artery bypass surgery) and classified their cause as in-stent restenosis or stent thrombosis based on review of angiograms and patient files. An independent endpoint committee, also blinded to treatment assignment, reviewed all events and classified all myocardial infarctions and deaths.

Continuous variables with a normal distribution were analyzed using the two-sample t-test (Cochran t-test if the variances were unequal) and continuous variables with a non-normal distribution using the Mann-Whitney U test. Categorical variables were analyzed using the Chi-square test. Endpoints were counted in the follow-up period starting on the date of the index PCI. For each endpoint, follow up continued until occurrence of the endpoint event, death, emigration, or until 18 months after stent implantation. We estimated relative risks using Cox proportional hazards regression analysis. In the analyses, patients receiving the sirolimus-eluting stent served as reference group. Analyses were performed according to the intention-to-treat principles. We used SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA) and p < 0.05 was considered statistically significant.

Results

Among the 2,332 patients randomized to zotarolimus-eluting or sirolimus-eluting stents in the SORT OUT III trial, 695 received PCI for multiple (> 1) lesions at the index PCI. Of these, 350 were allocated to zotarolimus-eluting stents and 345 were allocated to sirolimus-eluting stents. Baseline patient characteristics were well-balanced between the zotarolimus-eluting and sirolimus-eluting stent groups with the exception of previous PCI which was more common among those receiving zotarolimus-eluting stents (Table 1). In total, 810 lesions were treated in the zotarolimus-eluting stent group and 787 lesions were treated in the sirolimus-eluting stent group with similar lesion and procedure data, except for a small difference in the distribution of the number of treated lesions per patient (Table 2).

Table 1. Baseline clinical characteristics

Table 2. Lesion and procedure data

The assigned study stent could not be implanted in 1 lesion in a patient allocated to the zotarolimus-eluting stent and in 11 lesions in patients allocated to the sirolimus-eluting stent. This was a statistically significant difference in stent deliverability (Table 2).

All endpoints occurred more frequently in patients treated with zotarolimus-eluting stents (Table 3, Figure 1). For MACE, all cause death, myocardial infarction, TVR, TLR, and in-stent restenosis, the differences were statistically significant. For cardiac death and definite stent thrombosis, the differences were not statistically significant but the hazard ratios were high and in favor of the sirolimus-eluting stent (6.97 and 4.01, respectively).

Table 3. Clinical endpoints

thumbnailFigure 1. Major adverse cardiac events (MACE) and target lesion revascularization (TLR) Kaplan-Meier curves. MACE encompassed cardiac death, myocardial infarction, and target vessel revascularization.

Discussion

In the present SORT OUT III sub-study, we observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent. The difference was consistent across all endpoints. Thereby, this study extends findings from previous studies to patients in need of intervention for multiple lesions [7].

Comparing the difference in clinical outcomes in the current analysis with the overall SORT OUT III study results [5], higher hazard ratios were observed for all endpoints. The hazard ratio for MACE was more than two times higher than in the overall results. The hazard ratios for all other endpoints were 1.6 (in-stent restenosis) to 4.6 (cardiac death) times higher than in the overall results. In accordance with the overall results, the outcome differences were statistically significant for MACE, all cause death, myocardial infarction, TVR, TLR, and in-stent restenosis while the differences were not statistically significant for cardiac death and definite stent thrombosis.

The observed larger difference in outcome in patients treated for multiple lesions compared to the overall results supports the relatively consistent findings in favor of the sirolimus-eluting stent [18]. Our findings are also in agreement with a subgroup analysis of the SPIRIT III trial. In SPIRIT III, the outcome among patients treated with the everolimus-eluting stent (XIENCE V) and the paclitaxel-eluting stent (TAXUS) were compared favoring the everolimus eluting stent [19]. In a subgroup analysis of patients treated for 2-vessel disease in SPIRIT III, patients treated for 2-vessel disease had a larger outcome difference in favor of the everolimus-eluting stent compared to those treated for 1-vessel disease [20].

With a true outcome difference in patients with single lesions, a similar or even more favorable outcome difference in patients with multiple lesions in general then seems likely. However, there may be effects that could not have been predicted from studies on patients with single lesions and therefore subgroup analyses or specifically designed studies should be performed in patients with multiple lesions. Also, any trial can be associated with a type 1 error, and confirmation of a trial result in similar or associated settings is always settling.

The different event rates observed could be caused by differences in drugs, drug release kinetics, polymers, or other factors related to stent design. Any of these parameters could affect plaque or vessel wall healing and thus have impact on the results. This study, however, was not designed to assess these mechanisms. Likewise, differences in stent deliverability may be attributed to many factors in stent design.

There are some limitations to our study. The SORT OUT III parent study was powered to assess the composite clinical endpoint, MACE, at 9-month follow-up [5]. Therefore, this sub-study relying on the SORT OUT III data after 18 months of follow-up was not necessarily powered to assess the examined endpoints. As well, the results obtained in this study for the rapid-release Endeavor™ stent cannot be extrapolated to other zotarolimus-eluting stents such as the slow-release Resolute™ stent [21]. The SORT OUT III trial [5], like the SORT OUT II trial [22], relied on registry-based event detection without study-related angiographic or clinical follow-up. Patient follow-up care was in accordance with normal clinical practice, i.e., a standard clinical outpatient visit at the referring hospital after 1-3 months. This patient-driven event detection reflects event presentation in routine clinical practice where patients need to contact the heath care system. This methodology thus differs from event detection based on study-driven telephone calls or visits at outpatient clinics.

Conclusions

We observed better clinical outcomes among patients treated for multiple lesions with the sirolimus-eluting stent compared to those treated with the zotarolimus-eluting stent.

Abbreviations

PCI: percutaneous coronary intervention; DES: drug eluting stent(s); MACE: major adverse cardiac events; TVR: target vessel revascularization; TLR: target lesion revascularization.

Competing interests

MM has received lecture fees from Cordis, and consultant fees from Medtronic. JFL has received consultant fees from Boston Scientific, Guidant, Abbott, Terumo, St Jude medical and Cordis, and has received unrestricted research grant support from Abbott, Boston Scientific, Cordis, Medtronic, St Jude medical and Terumo. AK has received lecture fees from Cordis. LOJ has received lectures fees from Abbott and Cordis. JR has received consultant fees from Abbott and Cordis, and has received unrestricted research grant support from Abbott, Boston Scientific, Cordis, Medtronic and Terumo. LT has received lecture fees from Medtronic, Abbott, Cordis, and Boston Scientific; he also received consultant fees from Abbott and he is on the advisory board of Boston Scientific, and has received unrestricted research grant support from Medtronic, Abbott, Cordis, and Boston Scientific. All other authors declared no conflicts of interest.

Authors' contributions

TT: analysis, interpretation of data, drafting the manuscript. MM: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. JFL: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. AK: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. LOJ: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. JR: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. PT: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. SG: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. EHC: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. TE: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. MM: conception and design, analysis, interpretation of data, revision of manuscript. LT: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. HHT: conception and design, acquisition of data, analysis, interpretation of data, revision of manuscript. All authors read and approved the final manuscript.

Acknowledgements

This work was supported by unrestricted grants from Cordis and Medtronic.

References

  1. Wijns W, Kolh P, Danchin N, Di MC, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, et al.: Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).

    Eur Heart J 2010, 31:2501-2555. PubMed Abstract | Publisher Full Text OpenURL

  2. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Stahle E, Feldman TE, van den Brand M, Bass EJ, et al.: Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.

    N Engl J Med 2009, 360:961-972. PubMed Abstract | Publisher Full Text OpenURL

  3. Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O'Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, 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. PubMed Abstract | Publisher Full Text OpenURL

  4. Windecker S, Remondino A, Eberli FR, Juni P, Raber L, Wenaweser P, Togni M, Billinger M, Tuller D, Seiler C, et al.: Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization.

    N Engl J Med 2005, 353:653-662. PubMed Abstract | Publisher Full Text OpenURL

  5. Rasmussen K, Maeng M, Kaltoft A, Thayssen P, Kelbaek H, Tilsted HH, Abildgaard U, Christiansen EH, Engstrom T, Krusell LR, et al.: Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial.

    Lancet 2010, 375:1090-1099. PubMed Abstract | Publisher Full Text OpenURL

  6. Park DW, Kim YH, Yun SC, Kang SJ, Lee SW, Lee CW, Park SW, Seong IW, Lee JH, Tahk SJ, et al.: Comparison of zotarolimus-eluting stents with sirolimus- and paclitaxel-eluting stents for coronary revascularization: the ZEST (comparison of the efficacy and safety of zotarolimus-eluting stent with sirolimus-eluting and paclitaxel-eluting stent for coronary lesions) randomized trial.

    J Am Coll Cardiol 2010, 56:1187-1195. PubMed Abstract | Publisher Full Text OpenURL

  7. Garg S, Serruys PW: Coronary stents: current status.

    J Am Coll Cardiol 2010, 56:S1-42. PubMed Abstract | Publisher Full Text OpenURL

  8. Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation.

    Journal of Chronic Diseases 1987, 40:373-383. PubMed Abstract | Publisher Full Text OpenURL

  9. Charlson M, Szatrowski TP, Peterson J, Gold J: Validation of a combined comorbidity index.

    J Clin Epidemiol 1994, 47:1245-1251. PubMed Abstract | Publisher Full Text OpenURL

  10. Kaltoft A, Jensen LO, Maeng M, Tilsted HH, Thayssen P, Bottcher M, Lassen JF, Krusell LR, Rasmussen K, Hansen KN, et al.: 2-year clinical outcomes after implantation of sirolimus-eluting, paclitaxel-eluting, and bare-metal coronary stents: results from the WDHR (Western Denmark Heart Registry).

    J Am Coll Cardiol 2009, 53:658-664. PubMed Abstract | Publisher Full Text OpenURL

  11. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A: Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents.

    Circulation 1994, 90:583-612. PubMed Abstract | Publisher Full Text OpenURL

  12. Sørensen HT: Regional administrative health registries as a resource in clinical epidemiology.

    International Journal of Risk and Safety in Medicine 1997, 10:1-22. OpenURL

  13. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH: The Danish National Hospital Register. A valuable source of data for modern health sciences.

    Dan Med Bull 1999, 46:263-268. PubMed Abstract OpenURL

  14. Juel K, Helweg-Larsen K: The Danish registers of causes of death.

    Dan Med Bull 1999, 46:354-357. PubMed Abstract OpenURL

  15. Frank L: Epidemiology. When an entire country is a cohort.

    Science 2000, 287:2398-2399. PubMed Abstract | Publisher Full Text OpenURL

  16. Madsen M, Davidsen M, Rasmussen S, Abildstrom SZ, Osler M: The validity of the diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality and hospital discharge data with the Danish MONICA registry.

    J Clin Epidemiol 2003, 56:124-130. PubMed Abstract | Publisher Full Text OpenURL

  17. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB: The Danish Civil Registration System. A cohort of eight million persons.

    Dan Med Bull 2006, 53:441-449. PubMed Abstract OpenURL

  18. Hill AB: The environment and disease: association or causation?

    Proc R Soc Med 1965, 58:295-300. PubMed Abstract | PubMed Central Full Text OpenURL

  19. Stone GW, Midei M, Newman W, Sanz M, Hermiller JB, Williams J, Farhat N, Caputo R, Xenopoulos N, Applegate R, 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. PubMed Abstract | Publisher Full Text OpenURL

  20. Applegate RJ, Hermiller JJ, Sanz M, Doostzadeh J, Pierson W, Su X, Lansky AJ, Sudhir K, Stone GW: Comparison of everolimus-eluting and paclitaxel-eluting coronary stents in patients with two treated vessels: 2-year results from the SPIRIT III randomised trial.

    EuroIntervention 2010, 6:437-446. PubMed Abstract | Publisher Full Text OpenURL

  21. Serruys PW, Silber S, Garg S, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van Boven AJ, Hofma SH, Linke A, et al.: Comparison of zotarolimus-eluting and everolimus-eluting coronary stents.

    N Engl J Med 2010, 363:136-146. PubMed Abstract | Publisher Full Text OpenURL

  22. Galloe AM, Thuesen L, Kelbaek H, Thayssen P, Rasmussen K, Hansen PR, Bligaard N, Saunamaki K, Junker A, Aaroe J, et al.: Comparison of paclitaxel- and sirolimus-eluting stents in everyday clinical practice: the SORT OUT II randomized trial.

    JAMA 2008, 299:409-416. PubMed Abstract | Publisher Full Text OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2261/12/18/prepub