Correspondence
Treatment of Restenosis with a Paclitaxel-Coated Balloon Catheter
N Engl J Med 2007; 356:1071-1073March 8, 2007
- Article
To the Editor:
We question the conclusion by Scheller and colleagues (Nov. 16 issue)1 that paclitaxel-coated balloon catheters significantly reduce the incidence of adverse outcomes in patients undergoing percutaneous coronary intervention for in-stent stenosis. First, the trial was reported to be a double-blind study, but the investigators were aware of assignments to study groups because the paclitaxel-coated balloons were a different color from the uncoated balloons. The reduction in major cardiac events in patients who received treatment with a paclitaxel-coated balloon was driven primarily by a reduction in target-lesion revascularization, a subjective end point that was based on symptoms and angiographic appearance reported by investigators who were aware of study-group assignments. Two of the authors were also coinventors on a patent for the paclitaxel-coated balloon evaluated in the study.
Second, the clinical relevance of a reduction in restenosis is uncertain. In-stent stenosis is usually a nonfatal condition,2 and the use of drug-eluting stents to reduce restenosis may lead to a late increase in the rate of death from noncardiac causes.3 Adequately powered and blinded randomized clinical studies with extended follow-up are required to demonstrate both the efficacy and the safety of paclitaxel-coated balloon catheters.
3 ReferencesJack C.J. Sun, M.D.
John W. Eikelboom, M.D.
McMaster University, Hamilton, ON L8L 2X2, Canada
sunjc2@mcmaster.ca 1
Scheller B ,Hehrlein C ,Bocksch W , et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355:2113-2124
Full Text | Web of Science | Medline2
Ryan J ,Cohen DJ . Are drug-eluting stents cost-effective? It depends on whom you ask. Circulation 2006;114:1736-1744
CrossRef | Web of Science | Medline3
Nordmann AJ ,Briel M ,Bucher HC . Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a meta-analysis. Eur Heart J 2006;27:2784-2814
CrossRef | Web of Science | Medline
To the Editor:
Although we agree with the opinion of Camenzind in the editorial1 accompanying the article by Scheller at al., we are concerned about the information shown in Fig. 1, which we believe is not evidence-based. In Panel A, late luminal loss is graphically represented as a “normal” curve. Although late luminal loss is commonly expressed as a mean ±SD, the distribution of late luminal loss is not “normal” but “bimodal.”2,3 This also is true of drug-eluting stents.4,5 Thus, the relationships among late luminal loss, binary restenosis, and repeated revascularization are more complex than they appear in Panel A.5
In Panel B, a J-curve relationship between late luminal loss and clinical events is represented. The hypothesized increase in the rate of death or infarction with negative late luminal loss has never been proved, and the sentence “Late thrombosis causing myocardial infarction or death is more likely to occur among patients with minimal or negative late luminal loss” is not evidence-based.
Late luminal loss is a simple bidimensional measure that is used as a surrogate for a complex three-dimensional phenomenon. It has inherent limitations.5 The use of late luminal loss as a surrogate for stent endothelialization is inaccurate, since evidence correlating these measures is lacking.
5 ReferencesPierfrancesco Agostoni, M.D.
Antwerp Cardiovascular Institute Middelheim, 2020 Antwerp, Belgium
agostonipf@gmail.com Giuseppe M. Sangiorgi, M.D.
EMO Centro Cuore Columbus, 20100 Milan, ItalyGiuseppe G. Biondi-Zoccai, M.D.
University of Turin, 10100 Turin, Italy1
Camenzind E . Treatment of in-stent restenosis -- back to the future? N Engl J Med 2006;355:2149-2151
Full Text | Web of Science | Medline2
Lehmann KG ,Melkert R ,Serruys PW . Contributions of frequency distribution analysis to the understanding of coronary restenosis: a reappraisal of the gaussian curve. Circulation 1996;93:1123-1132
Web of Science | Medline3
Schomig A ,Kastrati A ,Elezi S , et al. Bimodal distribution of angiographic measures of restenosis six months after coronary stent placement. Circulation 1997;96:3880-3887
Web of Science | Medline4
Lemos PA ,Mercado N ,van Domburg RT ,Kuntz RE ,O'Neill WW ,Serruys PW . Comparison of late luminal loss response pattern after sirolimus-eluting stent implantation or conventional stenting. Circulation 2004;110:3199-3205
CrossRef | Web of Science | Medline5
Agostoni P, Cosgrave J, Biondi-Zoccai GG, et al. Angiographic analysis of pattern of late luminal loss in sirolimus and paclitaxel eluting stents. Am J Cardiol (in press).
Author/Editor Response
With regard to the comments of Sun and Eikelboom: the aim of our trial was to study paclitaxel-coated balloon catheters for the first time in patients. The primary end point, late luminal loss on angiography, was evaluated by an independent, blinded core laboratory without knowledge of the treatment group to which the patients were randomly assigned. Angiographic analysis indicated that paclitaxel-coated balloons were effective in reducing late luminal loss. It is a common understanding that conclusions concerning all analyses of secondary end points (such as the analysis of clinical events in our trial) are exploratory.
According to the randomization procedure described in our article, six balloon catheters of different sizes, either coated or uncoated, were packed in identically labeled sets carrying the randomization number on each set. The sterile packages with the catheters were opened only after a patient had been assigned to a random number. Thus, the blinded selection of patients for both study groups was guaranteed. It is hard to do better in a trial comparing devices of somewhat different appearance.
In their second comment, Sun and Eikelboom refer to an ongoing discussion of the safety of drug-eluting stents, which was not the subject of our study. We do agree that larger and longer trials will be necessary to confirm the benefits suggested by the initial report; this point was acknowledged in our discussion.
Bruno Scheller, M.D.
Michael Böhm, M.D.
Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany
bruno.scheller@uks. eu Author/Editor Response
With respect to the comments of Agostoni et al.: the figure in the editorial depicts a concept whose message is not dependent on the best mathematical fit of the distribution curve of late luminal loss. The intent was, rather, to illustrate the shift of the distribution curve to the left as a consequence of treatment approaches that inhibit restenosis. Thus, with such therapies, vascular widening develops in a larger portion of the treated population, which is reflected in a larger negative area of late luminal loss. This phenomenon reflects an abnormal healing response previously observed after brachytherapy for the treatment of restenosis; the clinical consequences of this response have been well documented.1,2
We are discovering that any potent, site-specific approach to treatment that interferes with arterial healing3 may create a potential local prothrombotic milieu and carry the clinical risk of myocardial infarction and death.4 The issue is important because angiographic findings have been traditionally used in interventional cardiology as surrogate end points for the clinical outcome. However, excellent luminal results (negative late luminal loss) may predict a worse clinical outcome (as shown by the J curve), suggesting that an established principle of therapeutics is seen with endovascular interventions: the more potent the treatment, the stronger the adverse effect.
4 ReferencesEdoardo Camenzind, M.D.
University of Geneva, 1211 Geneva, Switzerland
edoardo@camenzind-cardio.net 1
Waksman R ,Ajani AE ,White RL , et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001;103:2332-2335
Web of Science | Medline2
Serruys PW ,Wijns W ,Sianos G , et al. Direct stenting versus direct stenting followed by centered beta-radiation with intravascular ultrasound-guided dosimetry and long-term anti-platelet treatment: results of a randomized trial: Beta-Radiation Investigation with Direct Stenting and Galileo in Europe (BRIDGE). J Am Coll Cardiol 2004;44:528-537
CrossRef | Web of Science | Medline3
Joner M ,Finn AV ,Farb A , et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202
CrossRef | Web of Science | Medline4
Iakovou I ,Schmidt T ,Bonizzoni E , et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Oscar Semeraro, Pierfrancesco Agostoni, Stefan Verheye, Glenn Van Langenhove, Paul Van den Heuvel, Carl Convens, Frank Van den Branden, Nico Bruining, Paul Vermeersch. (2009) Re-examining minimal luminal diameter relocation and quantitative coronary angiography – intravascular ultrasound correlations in stented saphenous vein grafts: methodological. EuroIntervention 4:5, 633-640
CrossRef2
Giuseppe Biondi-Zoccai, Pierfrancesco Agostoni, Claudio Moretti, Emanuele Meliga, Imad Sheiban. (2007) Making sense of the recent meta-analytical confusion concerning the safety of drug-eluting stents. EuroIntervention 3:3, 381-385
CrossRef
