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(Circulation. 2005;111:e370-e371.)
© 2005 American Heart Association, Inc.

Correspondence

Letters Regarding Article by Mehilli et al, "Randomized Clinical Trial of Abciximab in Diabetic Patients Undergoing Elective Percutaneous Coronary Interventions After Treatment With a High Loading Dose of Clopidogrel"

Áurea J. Chaves, MD; Amanda G.M.R. Sousa, MD

Invasive Cardiology Section, Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil

To the Editor:

Mehilli et al¹ reported that abciximab did not reduce death or myocardial infarction after percutaneous intervention in diabetics pretreated with a 600-mg loading dose of clopidogrel, but that it reduced restenosis in the subgroup treated with bare-metal stents (BMS). We previously reported that abciximab was not associated with a reduction of in-stent intimal hyperplasia measured by intravascular ultrasound in patients with diabetes treated with BMS. In-stent volume obstruction, a surrogate for in-stent restenosis, did not differ between patients with diabetes treated with or without abciximab.² In an attempt to reconcile these data, we found that some aspects of the ISAR-SWEET study need to be clarified.

First, the analysis of restenosis was done on a per-lesion basis rather than on a per-patient basis. The statistical tests used assumed that lesions within the same patient are independent for restenosis. We learned from Kastrati et al,³ however, that there is an interlesion dependence of restenosis in patients who undergo multilesion intervention (the probability of restenosis for a lesion being higher when a companion lesion has also developed restenosis). Hence, it follows that the correlation among lesions within patients had to be considered and an alternative statistical model that takes into account the correlations applied (eg, linear mixed-effect models). Second, the angiographic results were presented for the groups as a whole, including lesions treated with balloons and drug-eluting stents. Although the study was randomized, it is uncertain whether patients treated with BMS were balanced regarding the angiographic and procedural characteristics. Finally, variables known to influence in-stent restenosis, such as the stented segment length and the stent types used, were not mentioned.

We think that such an analysis would allow a more reliable exploration of what effect, if any, abciximab had in the reduction of in-stent restenosis in patients with diabetes.

	References

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1. Mehilli J, Kastrati A, Schuhlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schomig A; Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation. 2004; 110: 3627–3635.[Abstract/Free Full Text]
   
2. Chaves AJ, Sousa AGMR, Mattos LA, Abizaid A, Staico R, Feres F, Centemero M, Tanajura LF, Abizaid A, Pinto I, Maldonado G, Seixas A, Costa MA, Paes A, Mintz GS, Sousa JE. Volumetric analysis of in-stent intimal hyperplasia in diabetic patients treated with or without abciximab: results of the Diabetes Abciximab steNT Evaluation (DANTE) randomized trial. Circulation. 2004; 109: 861–866.[Abstract/Free Full Text]
   
3. Kastrati A, Schömig A, Elezi S, Schuhlen H, Wilhelm M, Dirschinger J. Interlesion dependence of the risk for restenosis in patients with coronary stent placement in multiple lesions. Circulation. 1998; 97: 2396–2401.[Abstract/Free Full Text]
   

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John W. Eikelboom, MD

McMaster University, Hamilton, Canada

James M. Rankin, MD

Royal Perth Hospital, Perth, Australia

To the Editor:

We congratulate Dr Mehilli and colleagues for completing the Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) trial¹ without the support of industry. Their results suggest that there is no incremental benefit of abciximab in patients with diabetes undergoing percutaneous coronary intervention (PCI) who are pretreated with a 600-mg loading dose of clopidogrel. There are, however, several reasons to be cautious in drawing such conclusions.

First, ISAR-SWEET was designed as a superiority trial to detect a 50% reduction in myocardial infarction or death. Even a 25% risk reduction is clinically worthwhile but would have required >3500 patients to be reliably detected. Therefore, the ISAR-SWEET results do not exclude a worthwhile incremental benefit of abciximab in patients with diabetes undergoing PCI.

Second, even if ISAR-SWEET had demonstrated equivalence or noninferiority of placebo as compared with abciximab, this cannot necessarily be attributed to a higher loading dose of clopidogrel; the types of patients studied or use of other co-interventions could also potentially account for such a finding.

Third, there are emerging data that the extent of adenosine phosphatase receptor inhibition by clopidogrel varies according to dose and predicts outcome.² Despite this, it remains to be established in randomized trials whether increasing the dose of clopidogrel improves efficacy without compromising safety.

To establish whether increasing the loading dose of clopidogrel to 600 mg can avoid the need for a glycoprotein IIb/IIIa inhibitor during PCI requires randomized comparison of a glycoprotein IIb/IIIa inhibitor versus placebo in patients who are randomized to a 600-mg versus a 300-mg (standard) loading dose of clopidogrel. This could be readily achieved with a factorial design, but it would require many thousands of patients to be randomized.

We have been using aspirin for >30 years to prevent cardiovascular disease, but there is still debate about the optimal therapeutic dose. The same question is increasingly being asked about clopidogrel and will be definitively answered only by appropriately powered randomized comparisons of different clopidogrel doses. This is a critically important issue because cardiovascular disease is the most common cause of death and long-term disability worldwide, and even small differences in efficacy or safety of secondary preventive strategies will have a large impact on morbidity and mortality at a population level.

	References

Top References References  References

 

1. Mehilli J, Kastrati A, Schuhlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schomig A; Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation. 2004; 110: 3627–3635.[Abstract/Free Full Text]
   
2. Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation. 2004; 109: 3064–3067.[Free Full Text]
   

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Response

Adnan Kastrati, MD; Julinda Mehilli, MD; Helmut Schühlen, MD; Alban Dibra, MD; Jürgen Pache, MD; Albert Schömig, MD

Deutsches Herzzentrum, Munich, Germany

Nicolas von Beckerath, MD; Hildegard Bollwein, MD; Josef Dirschinger, MD

Medizinische Klinik rechts der Isar, Munich, Germany

Franz Dotzer, MD

Medizinische Klinik I, Garmisch-Partenkirchen, Germany

Peter P. Berger, MD

Duke Clinical Research Institute, Durham, NC

We appreciate Drs Chaves, Sousa, Eikelboom, and Rankin’s comments on ISAR-SWEET.¹ Drs Chaves and Sousa request a lesion-based analysis of restenosis that accounts for intrapatient correlation. We constructed a logistic regression model of angiographic restenosis including all clinical, angiographic, and procedural characteristics presented in Tables 1 and 2 from our article¹ as covariates. To eliminate a potential clustering effect in patients with multilesion intervention, bootstrapping with 1000 replications was applied for the calculation of regression coefficients, odds ratios (OR), and 95% confidence intervals (CI). On the basis of the results of this analysis, assignment to the abciximab group was associated with an adjusted OR of 0.68 [95% CI, 0.48 to 0.96] for restenosis as compared with placebo. No interaction was observed between treatment effect and form of the intervention performed (stenting or plain balloon angioplasty) with respect to angiographic restenosis (P=0.19). None of the variables listed in Table 2 of the original article¹ were different between the 2 study groups when the analysis was restricted to lesions treated with bare-metal stents. Specifically, neither stent type (P=0.35) nor stented segment length (P=0.46) differed between the abciximab and placebo groups.

Drs Eikelboom and Rankin raise several important issues. We would underscore that ISAR-SWEET was the largest-ever randomized trial on percutaneous coronary interventions (PCI) in patients with diabetes and that the assumed risk reduction of 50% has been a typical finding with abciximab during coronary stenting.² We agree, however, that a larger sample size would have provided our trial with sufficient power to detect a smaller risk reduction, in particular in the subset of insulin-treated patients. Drs Eikelboom and Rankin write that there are no data in support of increased clinical efficacy and maintained safety with a 600-mg loading dose of clopidogrel versus a 300-mg loading dose. This raises an important issue that is misunderstood by many. A 600-mg loading dose of clopidogrel achieves a degree of platelet inhibition comparable to that shown for chronic clopidogrel therapy;³; thus, there is no reason for more safety concerns after 600 mg than with chronic clopidogrel treatment. The benefit of using a higher loading dose of clopidogrel is believed to be the more rapid inhibition of platelet aggregation, which is highly desirable during PCI. There is, however, growing evidence in support not only of the safety of 600-mg clopidogrel loading⁴ but also of its superiority in terms of efficacy compared with a 300-mg loading dose when first administered 4 to 8 hours pre-PCI.⁵

	References

Top References References  References

 

1. Mehilli J, Kastrati A, Schuhlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PP, Schomig A; Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation. 2004; 110: 3627–3635.[Abstract/Free Full Text]
   
2. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet. 1998; 352: 87–92.[Medline] [Order article via Infotrieve]
   
3. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schömig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. 2004; 110: 1916–1919.[Abstract/Free Full Text]
   
4. Kastrati A, Mehilli J, Schühlen H, Dirschinger J, Dotzer F, ten Berg JM, Neumann FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schömig A. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med. 2004; 350: 232–238.[Abstract/Free Full Text]
   
5. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005; 111: 2099–2106.[Abstract/Free Full Text]
   

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