Gone But Not ForgottenThe Case for Drug-Eluting Stents in Percutaneous Revascularization of the Chronic Coronary Total Occlusion*
James E. Tcheng, MD*,
David A. Zidar, MD, PhD
Duke University Medical Center, Durham, North Carolina
Key Words: chronic total occlusion • percutaneous coronary intervention • drug-eluting stent • coronary stent
The granting of regulatory approval for the treatment of coronary artery disease with drug-eluting stents has proven to be a hallmark event in interventional cardiology. Given the dramatic efficacy of these devices in reducing restenosis, the interventional community has rapidly extended the application of drug-eluting stents beyond the "approved," but relatively straightforward, nonocclusive lesion types studied in pivotal registration trials (1,2) to "off-label" indications including the chronic total occlusion. To date, few studies have addressed the efficacy and safety of drug-eluting stent implantation in these extended indications. The study by De Felice et al. (3), in this issue of JACC: Cardiovascular Interventions, helps fill a critical gap of our medical knowledgebase regarding drug-eluting stents in complex coronary lesion subsets.
Given the physical and physiologic properties of drug-eluting stents, coupled with the extensive body of evidence demonstrating reductions in angiographic restenosis and clinical target lesion and target vessel revascularization, it should come as no surprise that the primary finding of the study is also a reduction in target lesion revascularization (8% vs. 21%, p < 0.004). Even given the limitations of the sequential cohort, nonrandomized registry design, this is indeed good news—especially the <10% rate of (clinically driven) repeat target lesion interventions. Previous prospective randomized trials of (early generation) bare-metal stents versus balloon angioplasty, including the SICCO (Stenting in Chronic Coronary Occlusion), GISSOC (Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche), TOSCA (Total Occlusion Study of Canada), and PRISON (Primary Stenting of Totally Occluded Native Coronary Arteries) trials (4–8) (Table 1), demonstrated relatively unacceptable rates of target lesion revascularization with bare-metal stent implantation. In these studies, whereas bare-metal stent implantation reduced restenosis compared with balloon percutaneous coronary intervention, the high late loss index of stent implantation resulted in absolute rates of angiographic restenosis of 22% to 55%. Furthermore, the problem of reocclusion (not just restenosis) did not appear to be solved by bare-metal stent implantation, with 8% to 16% rates of occlusion observed in these trials. Whereas the target lesion revascularization end point used in the current study is obviously not angiographic restenosis, and the design did not mandate angiographic follow-up, the clinically relevant reduction in target lesion revascularization nonetheless undoubtedly reflects a proportionate reduction in true vascular restenosis in this lesion subset.
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Table 1 Quantitative Coronary Analysis of Randomized Trials of Balloon Angioplasty Versus Bare-Metal Stent Intervention for Coronary Total Occlusions
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Even given the positive finding of a reduction in restenosis to what most would consider an acceptable level, the advantages of drug-eluting stent implantation, unfortunately, do not appear to extend much beyond that singular finding. Interestingly, this echoes the clinical end point findings of the bare-metal stent versus balloon angioplasty trials—that there may be little clinical benefit of stent implantation in chronic coronary total occlusion beyond reducing restenosis and (presumably) improving symptomatology. For example, in the TOSCA trial, there was no statistically significant difference in 1-year mortality (0.5% in the balloon angioplasty cohort vs. 1.5% in the stent cohort, p = NS), whereas rates of protocol-defined myocardial infarction at 1 year were actually higher in the stent group (3.8% vs. 12.4%, p = 0.012). It is this propensity for delayed events that was hinted at in the contrasting findings of the 1- versus 3-year reports from the RESEARCH (Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital) study as reported by Hoye et al. (9) and Garcia-Garcia et al. (10), respectively. Between the 1-year and 3-year time points in the RESEARCH study, there was a loss of the advantage of drug-eluting stent implantation with respect to target lesion revascularization and major adverse cardiac events. Fortunately, this reversal of fortune was not seen in the current study, with no differences observed in either the 3-year overall major adverse cardiac event rates or the mortality or myocardial infarction components. Even with that, the time line for the 3 cases of stent thrombosis in the bare-metal stent patients (between 1 and 8 months) versus the 4 cases of stent thrombosis in the drug-eluting stent group (all occurring between 22 and 33 months) bears mentioning. It thus remains an overall limitation that lowered rates of restenosis have generally not translated into further decrements in myocardial infarction or mortality, whether in simple or complex clinical or anatomic subsets.
These arguments then bring into question the general efficacy of percutaneous coronary intervention of the chronically occluded coronary. Rather than appearing nihilistic, we instead hope that there remain additional clinical benefits that are simply undiscovered because of the limitations of existing study designs. In this vein, we believe the overall evidence accrued to date argues for use of drug-eluting stents in this anatomic subset. The key findings of the prospective, randomized PRISON II trial strongly contribute to this perspective. In PRISON II, 200 patients were randomized to the Cypher sirolimus-eluting stent (Cordis Corporation, Miami, Florida) versus the BxVelocity bare-metal stent (Cordis Corporation). The primary end point, binary restenosis at 1 year, was lower with the sirolimus drug-eluting stent (7% vs. 36%, p < 0.0001) (11). Importantly, the 3-year follow-up of PRISON II shows continued angiographic and overall clinical benefit in the sirolimus-eluting stent group (12).
So what else is needed to complete the picture? To the credit of De Felice et al. (3), a fairly rigorous definition of the eligible patient population was applied: documented total coronary occlusion of at least 3 months' duration coupled with demonstrable ischemia or viability. It is precisely this group (and not patients just with an angiographically documented total coronary occlusion) that deserves continued study. Furthermore, because the advantage of percutaneous coronary intervention may primarily be in the relief of symptoms, the constellation of "soft" end points reflecting symptomatology and other relevant elements should not be ignored; systematic inquiry regarding secondary end points (for example, angina status, heart failure incidence, rehospitalization rates, and medication usage) is needed. One plausible explanation for the lack of durability seen by García-García et al. (10) and its variance with this current study and PRISON II is that a greater appreciation now exists for extended antiplatelet therapy. The drug-eluting stent group may have been treated with a greater duration of dual antiplatelet therapy, which could have overestimated the impact of stent type on outcomes. Future studies will thus need to pay strict attention to the emerging importance of antiplatelet therapy in modulating long-term outcomes.
The obvious conclusion is that a large, parallel-group, prospective study is still needed. In the meantime, the welcome contributions of De Felice et al. (3) add to the growing body of evidence arguing for the use of drug-eluting stents in this off-label population.
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Footnotes
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* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. James E. Tcheng, Duke University Medical Center, 403 Hock Plaza, 2424 Erwin Road, Durham, North Carolina 27705 (Email: tchen001{at}mc.duke.edu).
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- García-García HM, Daemen J, Kukreja N, et al. Three-year clinical outcomes after coronary stenting of chronic total occlusion using sirolimus-eluting stents: insights from the rapamycin-eluting stent evaluated at Rotterdam cardiology hospital—(RESEARCH) registry Catheter Cardiovasc Interv 2007;70:635-639.[CrossRef][Web of Science][Medline]
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