Does the use of paclitaxel or rapamycin-eluting stent decrease further need for coronary-artery bypass grafting when compared with bare-metal stent?

ABSTRACT CONTEXT AND OBJECTIVE: The safety and efficacy of drug-eluting stents reduce the need for surgical revascularization. The objective of the present study was to investigate whether paclitaxel or rapamycin-eluting stent are effective in avoiding the need for coronary-artery bypass grafting. METHODS: This was a systematic review of the literature using the methodology of the Cochrane Collaboration. The type of study considered was controlled randomized trials; the type of intervention was drug-eluting or bare-metal stents; and the main outcome investigated was coronary-artery bypass grafting. RESULTS: The ten studies included in this systematic review did not show any statistically significant difference between the drug-eluting stents and the bare-metal stents with regard to the outcome of coronary-artery bypass grafting (confidence interval: 0.31 to 1.42). CONCLUSION: The surgical revascularization rate was not reduced by the use of drug-eluting stents.


INTRODUCTION
Restenosis following stent implantation is a consequence of neointimal hyperplasia resulting from the proliferation and migration of smooth-muscle cells and production of extracellular matrix.][3] There are two drugs commonly used: paclitaxel, a lipophilic molecule derived from the Pacific yew tree Taxus brevifolia that is capable of inhibiting cell division, motility, activation, secretory processes and signal transduction; and sirolimus (rapamycin), a cytostatic macrocyclic lactone with both anti-inflammatory and antiproliferative properties. 4Both restenosis and percutaneous revascularization are outcomes in all of the published studies.Drug-eluting stents appear to be a possibility for treating the coronary arterial disease, as a replacement for the existing therapies, but there is no proof of their effectiveness and safety.No differences in vital outcomes like mortality and myocardial infarction have been found between drug-eluting stents and bare-metal stents.However, such reports have not indicated whether there is any decrease in the need for coronary-artery bypass grafting (CABG).

OBJECTIVE
The objective of the present study was to investigate whether paclitaxel or rapamycineluting stents are effective in avoiding the need for CABG.

METHODS
The search strategy involved the following: a) online databases: Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Medical Literature Analysis and Retrieval System Online (Medline) and the Cochrane Library; b) manual search for studies; c) personal communication; and d) contact with the pharmaceutical industry.Two reviewers independently inspected the references of the studies found using this search strategy, and applied the inclusion criteria.Where disagreement occurred this was resolved by discussion or, if doubts remained, the full article was acquired for further inspection.An intention-to-treat analysis was done.The relative risks (RR) and their respective 95% confi dence intervals (CI) were calculated based on the random effects model, since this takes into account any differences between studies, even if there is no statistically signifi cant heterogeneity.The data were inspected to see whether analysis using a fi xed effects model would make any substantive difference.The methodological quality of the trials selected was assessed using the criteria described in the Cochrane Handbook. 5The Jadad scale 6 was also used.

Inclusion criteria Inclusion criteria
Type of study: Only randomized controlled trials were considered.The adequacy of allocation concealment was assessed as shown in Table 1.Only studies from categories A and B were considered for inclusion.
Type of participants: patients with restenosis post-stent implantation.
Type of interventions: drug-eluting stents versus bare-metal stents.
Type of outcome: coronary artery bypass grafting.
After locating all of the eligible studies, the data were summarized in a meta-analysis.This systematic review was approved by the ethics committee of Universidade Federal de São Paulo.

Included studies Included studies
The search strategy found 329 studies.Of these, 10 studies met the inclusion criteria that had been established.The excluded studies did not meet one or more of the inclusion criteria, particularly with regard to randomization and outcome.There was total agreement between the reviewers.

RESULTS
With regard to the outcome "need for coronary bypass grafting", the analysis was done in three subgroups: 1) polymer-based paclitaxeleluting stents; 2) polymer-free paclitaxel-eluting stents; 3) sirolimus (rapamycin)-eluting stents.There were 2,455 participants in the experimental group and 2,437 in the control group.In total, 10 included studies reported this outcome.Only one study, Taxus IV, was favorable to the experimental group.The data from each study were analyzed using the Rev-Man software. 17The resulting meta-analysis did not fi nd any statistically signifi cant difference between the drug-eluting stents and the baremetal stents: relative risk = 0.67; confi dence interval: 0.31 to 1.42 (Figure 1 -RevMan -Statistical analysis).
The following other outcomes were also analyzed in this study: Thrombosis: ten studies; none of them found any statistical difference for any group.Meta-analysis: relative risk = 1.1; confi dence interval: 0.48 to 2.12.
Mortality: ten studies; none of them found any statistical difference for any group.Meta-analysis: relative risk = 1.23; confi dence interval: 0.70 to 2.17.
Myocardial infarction: ten studies; none of them found any statistical difference for any group.Meta-analysis: risk relative = 0.84; confi dence interval: 0.61 to 1.17.

Table 1. Adequacy of allocation concealment of randomized controlled trial included
Percutaneous revascularization: ten studies; seven favorable to the experimental group and three without any statistical difference for any group.Meta-analysis: relative risk = 0.32; confi dence interval: 0.22 to 0.48; favorable to the experimental group.
Restenosis: ten studies; seven favorable to the experimental group and three without any statistical difference for any group.Meta-analysis: relative risk = 0.30; confi dence interval: 0.21 to 0.43; favorable to the experimental group.

DISCUSSION
This systematic review shows that there is no advantage in eluting stent over bare-metal stent.The literature shows that the trauma to the vessel wall that is caused by stent implantation triggers an infl ammatory endothelial response, independent of the presence or absence of a drug in this stent.This initial infl ammatory process is followed by a restenosis process. 18omparison between balloon angioplasty and coronary stenting shows that the infl ammatory process is less severe in balloon angioplasty, while in coronary stenting early neutrophil recruitment is followed by prolonged and abundant recruitment of macrophages within the neointima. 19,20After stenting, several infl ammatory markers are released [21][22][23] and their presence is associated with subsequent poor prognosis. 24dverse late clinical outcomes are linked with the magnitude of the systemic infl ammation.Patients may be risk-stratifi ed according to their concentrations of infl ammatory markers. 25Endothelial function becomes altered, thereby generating cytokine hypersecretion that preserves the infl ammatory process and leads to changes in the quantities of endothelial mediators released, which may decrease the nitric oxide levels (vasodilatation) or increase the endothelin-1 levels (vasoconstriction). 26,27tudies have shown that drug-eluting stents may exacerbate the inflammatory process, such that they may accentuate the restenosis process at the stent extremities 28 and boost the strength of some platelet agonists, thus promoting thrombus formation. 29Moreover, it has been demonstrated that sirolimus (rapamycin) reduces the production of nitric oxide. 30ll the transformations following stent implantation may persist for months and years.Clinically, there may or may not be any symptoms, but the important point is that these alterations exist and impair the clinical treatment.Consequently, it can be deduced that surgical revascularization in patients who have already been revascularized with stents, and whose hearts present chronic infl ammatory processes, will not have the same result as would be achieved in a heart that had never previously been revascularized with stents.In spite of the signifi cant differences in all restenosis measurements, which were favorable to paclitaxel and rapamycin-eluting stents, the surgical revascularization rate was similar in the experimental and control groups.
This was confi rmed at the recent World Congress of Cardiology held in Spain in September 2006.A meta-analysis with four years of follow-up was presented at that congress 31,32 (the published studies included in our systematic review had one-year follow-ups), in which the outcomes were similar to those presented in our systematic review, with the addition of other data that suggested that there was increased noncardiac mortality and a higher cancer rate in the experimental group.These poor outcomes confi rm all of the infl ammatory alterations that originate from stent implantation and their persistent disastrous consequences.
Taking all these facts together, it has to be accepted that the clinical benefi ts from drug-eluting stents with regard to target vessel restenosis and target vessel revascularization have been overestimated and that they do not offer safety, effi cacy and effectiveness.

CONCLUSION
In the present study, paclitaxel or rapamycin-eluting stent did not show any statistically signifi cant difference with regard to avoiding the need for coronary-artery bypass grafting, or in relation to myocardial infarction or death from cardiac causes, in comparison with bare-metal stent.