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European Heart Journal Advance Access originally published online on June 9, 2005
European Heart Journal 2005 26(16):1686-1687; doi:10.1093/eurheartj/ehi365
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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Critical role of bare-metal stent controls in trials of drug-eluting stents

Giuseppe G.L. Biondi-Zoccai

Interventional Cardiology Unit
St Raffaele Hospital
via Olgettina 60
20132 Milan, Italy
Tel: +39 3408626829
Fax: +39 0226437339
E-mail address: gbiondizoccai{at}gmail.com

Pierfrancesco Agostoni

Interventional Cardiology Unit
AZ Middelheim
Antwerpen
Belgium

Antonio Abbate

Department of Medicine
Medical College of Virginia
Richmond
VA
USA

Flavio Airoldi

Interventional Cardiology Unit
St Raffaele Hospital
via Olgettina 60
20132 Milan
Italy

Antonio Colombo

EMO Centro Cuore Columbus
Milan
Italy

We have read with interest the randomized trial comparing sirolimus-eluting stents (Cypher, Cordis) to thin-strut bare-metal stents (BMSs) (BeStent 2, Medtronic).1 Indeed, as the authors have previously pointed out, any novel treatment should be compared with the best performing control treatment, and thus, thin-strut BMS were the only correct benchmark for the thorough appraisal of drug-eluting stents (DESs).

In addition, results of the study from Pache et al.1 provide the first means to accurately test a novel and still controversial analytic tool, the adjusted indirect comparative meta-analysis.2 We have recently shown that, using their respective BMS control group as reference, different DESs can be indirectly compared by means of meta-analysis.3 Yet, any such comparison between DESs [namely Cypher vs. Taxus (Boston Scientific)] is based on the assumption that differences between their respective BMS controls [Bx Velocity (Cordis) and Express2 (Boston Scientific), respectively] have a negligible impact on the analysis. Our findings of a more pronounced anti-restenotic effect (P<0.001) in Cypher vs. Taxus have actually raised concerns that most of the relative risk reduction apparent with Cypher was due to the severely inferior performance of Bx Velocity (a well-known thick strut BMS) when compared with the substantially superior performance of Cypher [when compared with Express2 (a thinner strut BMS) and Taxus, respectively].

Using results reported from Pache et al.1 (Figure 1A), it can now be shown that the benefits obtained from Cypher vs. Bx Velocity are far greater than those obtained from Cypher vs. thin-strut BMS, thus casting a shadow of doubt on our indirect comparative results (P<0.0001 for statistical heterogeneity, when comparing the estimates obtained with thin-strut BMS vs. thick-strut BMS).




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  		Figure 1 (A) Testing the consistency between the odds ratio for the comparisons: (i) Bx Velocity (a thick-strut BMS) vs. Cypher (a polymer-based sirolimus-eluting Bx Velocity) and (ii) BeStent 2 (a thin-strut bare-metal stent) vs. Cypher. Heterogeneity and inconsistency tests suggest a strikingly different beneficial effect when using Cypher vs. Bx Velocity than when using Cypher vs. BeStent 2 [highly significant (P<0.01) for heterogeneity and severe inconsistency (I2>75%)], thus demonstrating that the use of a thick-strut BMS control is likely to overestimate the benefits of Cypher. (B) Preliminary results of a meta-analysis on the risk of binary angiographic restenosis with Cypher (a polymer-based sirolimus-eluting stent) vs. Taxus (a polymer-based paclitaxel-eluting stent) and pooling the latest direct head-to-head randomized trials. Combined estimates suggest a significant reduction in angiographic restenosis favouring Cypher (P<0.0001 for the overall effect) and thus, are in agreement with previous predictions based on adjusted indirect comparisons dating back as early as June 2004.3

 
Conversely, data recently reported from several direct head-to-head Cypher vs. Taxus randomized trials and demonstrating a lower risk of restenosis with Cypher vs. Taxus (P<0.0001) appear largely in agreement with our previous indirect adjusted findings (dating back as early as June 2004),4 both at graphical inspection and consistency testing with heterogeneity and inconsistency (I2) tests (Figure 1B). Nonetheless, some degree of overestimation cannot be dismissed and is likely due to the difference between thin- and thick-strut BMS, as correctly pointed out by Pache et al.1

In conclusion, the authors should be complimented for their independent research effort and for having reminded us that any piece of new clinical knowledge can provide important and relevant insights, both by itself and when combined with appropriate analytical methods in systematic overviews.5

References

  1. Pache A, Dibra A, Mehilli J, Dirschinger J, Schomig A, Kastrati A. Drug-eluting stents compared with thin-strut bare stents for the reduction of restenosis: a prospective, randomized trial. Eur Heart J 2005, in press. Published online ahead of print February 28, 2005. doi:10.1093/eurheartj/ehi098.
  2. Song F, Altman D, Glenny A-M, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analysis. BMJ 2003;326:472.[Abstract/Free Full Text]
  3. Biondi-Zoccai GGL, Agostoni P, Abbate A, Testa L, Burzotta F, Lotrionte M, Crea F, Biasucci LM, Vetrovec GW, Colombo A. Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare-metal-stent-controlled trias. Int J Cardiol 2005;100:119–123.[CrossRef][ISI][Medline]
  4. RevMan 4.2.4. The Cochrane Collaboration, Italian Cochrane Center, Milan, Italy. http://www.cochrane.org/software/download.htm
  5. Biondi-Zoccai GGL, Agostoni P, Abbate A. Parallel hierarchy of scientific studies in cardiovascular medicine. Ital Heart J 2003;4:819–820.[Medline]

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This Article
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