Is Implantation of Drug-Eluting Stents a Faustian Choice?

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Sorin J. Brener, MD

Faustian (fou’ stee-en) (adj) — from the Latin for lucky, auspicious; possessed with a hunger for knowledge or mastery (

As percutaneous coronary intervention (PCI) became the predominant method of revascularization in patients with symptomatic coronary artery disease, various obstacles to its widespread implementation and success became evident. Acute vessel closure related to extensive wall dissection led to acute vessel closure in 5–6% of patients within hours of balloon angioplasty. Coronary stents were designed specifically to prevent and treat this complication and became widely used. These devices also treated another less critical complication, namely the inherent propensity of injured vessels to engender a proliferative restenotic response, which affected 30–40% of patients. Thus, abrupt vessel closure was nearly eliminated and restenosis was reduced to 10–15% by the introduction of bare-metal stents (BMS). Further development of the stent platform witnessed the introduction of drug-eluting stents (DES), which resulted in a further reduction of restenosis to 4–5%. But there was a price to pay. Starting with the landmark report of 4 cases of late stent thrombosis (ST),1 and continuing with tens of additional publications, it became evident that the properties that allow DES to prevent restenosis also create the potential for ST, because of the markedly delayed, or absent, reendothelialization of the treated segment. Furthermore, the antirestenotic drugs eluted from the stents appear to affect endothelial function distal to the stent2,3 and further predispose certain patients to ST. The Academic Research Consortium (ARC) standardized the definitions, diagnosis and outcomes of ST4 and enabled researchers to compare their results in randomized clinical trials and in prospective registries of unselected patients. After a few years of intense research, the major predictors of ST and its consequences became well known to all interventional cardiologists.5,6 The decision to implant DES became less reflexive and practice guidelines of various societies exhorted us to verify that patients can have access to and tolerate dual antiplatelet therapy for a prolonged period of time, and that interruptions in this therapy are not expected in the first few months after stent implantation, thus addressing the important contributors to ST. Despite efforts to reduce the incidence of ST, first-generation DES remain associated with an indefinite excess of late ST of ~0.5% per year compared with BMS.7 Newer DES may have a lower propensity for this event, although there are not yet sufficient data to state this with certainty.8,9 Regardless of the type of DES or actual incidence, when ST occurs, it is associated with death or significant infarction in at least 40–60% of patients.10

In this issue, Blich and her colleagues11 present the data from a prospective institutional registry of 314 patients treated during 1 year at a tertiary medical center. Although all DES patients were included, it is very likely that a significant selection occurred prior to stent choice based on some national Israeli guidelines, as well as on patients’ characteristics and physician preference. The population treated was more “high risk” than those enrolled in clinical trials, as evidenced by a high incidence of acute coronary syndromes (73.3%), diabetes mellitus (44%) and multivessel CAD (62%). We do not have information on the stent deployment process (pressure, ultrasound confirmation of apposition) or adjunctive pharmacotherapy in these patients who predominantly received 1 DES (75%). After a median follow up of 2 years, 14 patients suffered definite or probable ST, although the exact frequency of each is not easy to glean. A third of those with ST died, accounting for half of all deaths, and 85% of all cardiac deaths, in this cohort. Three episodes of ST occurred before hospital discharge and did not result in death. The cases of ST were evenly distributed among the categories of early, late and very late, respectively. Importantly, 9 of the 14 cases occurred while on dual anti-platelet therapy. Temporary discontinuation of dual therapy for procedures did not result in ST in this cohort. None of these data are unique or unusual. The authors, though, did perform a multivariable analysis to identify predictors of ST and found that a history of a previous noncardiac thrombotic event was independently associated with ST (odds ratio 7.7, p = 0.006), a finding not previously reported. Minor bleeding was common (~20%), but hospitalization for bleeding was rare and blood transfusions were needed in only 6 patients. None of these events were related to death. There are no data to inform us on whether minor bleeding resulted in discontinuation of dual antiplatelet therapy, which could have led to ST. We are told, though, that among the 208 patients who discontinued clopidogrel at some point, only 5 developed ST at an average of 8 months after discontinuation.

At first glance, none of the findings in this study are new or contradictory to existing data, with the exception, perhaps, of the history of prior thrombotic event as a predictor of ST. Yet, one has to view even this “conforming” information with some skepticism. It is what is not in this report which should alert us to the limitations of single-institution registries. Notwithstanding the very small cohort size and the inherent wide confidence intervals for any of the events described, we are not told what happened to all the other patients treated with BMS during this period. How many of them died or had infarction? How many of them had ST? How many of them presented with acute coronary syndromes related to restenosis or had complications of repeat PCI? Only when we know those facts can we determine with more confidence whether the choice of DES in many of our patients is justified or not. Essentially, the choice of stent type in PCI patients is a risk-benefit decision, informed by patient- and procedure-specific characteristics. As Dr. Blich mentions, patients with high-risk characteristics for restenosis were usually selected for DES. Yet, there is no group of patients in whom DES does not reduce restenosis and need for reintervention.12 It is the magnitude and the economic impact of this benefit that one needs to consider when deciding to use DES.

On the positive side, DES clearly reduce the need for reintervention by 35–50% and allow us to treat more complex lesions with the confidence that restenosis rates are not prohibitively high. The durability of this benefit seems to have improved with newer DES. In some registries, with propensity-matching for stent choice and long-term follow up, DES even provide a reduction in mortality compared to BMS.13 One should also consider the potential benefits of prolonged dual antiplatelet therapy beyond the protection from ST.14

On the negative side, DES implantation exposes the patient to the prolonged risk of bleeding and expense associated with dual antiplatelet therapy. Bleeding, even if minor, may lead to discontinuation of appropriate platelet inhibitors and predispose patients to ischemic events. It also prevents many patients from having additional noncardiac procedures, which may or may not be essential for their health. Because of the perceived risk of ST with even temporary discontinuation of antiplatelet therapy, and the catastrophic consequences if it occurs, much attention should be given to the selection of appropriate patients for DES implantation and to the education of patients and physicians on how to deal with the unexpected need for invasive procedures after DES implantation.

In summary, as the benefits and risks of DES continue to be defined, Dr. Blich’s report adds to what is known, but does not truly answer the questions of whether BMS implantation would have been preferred in this cohort. Only large, randomized clinical trials or multicenter registries with adequate cohort size and sufficiently extended follow-up periods can inform us on whether DES should be used in a majority of patients. In any case, this debate will end when better DES that do not increase the risk of ST become available.

It is the unquenchable thirst for knowledge and desire to improve outcomes rather than a compromise that lead us to this Faustian, or rather auspicious, choice.


1. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519–1521.

2. Kim JW, Seo HS, Park JH, et al. A Prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent: Differential recovery of coronary endothelial dysfunction. J Am Coll Cardiol 2009;53:1653–1659.

3. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007;115:1051–1058.

4. Cutlip DE, Windecker S, Mehran R, et al, on behalf of the Academic Research Consortium. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007;115:2344–2351.

5. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting Stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745–754.

6. 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.

7. Bavry AA, Kumbhani DJ, Helton TJ, et al. Late thrombosis of drug-eluting stents: A meta-analysis of randomized clinical trials. Am J Med 2006;119:1056–1061.

8. Leon MB, Kandzari DE, Eisenstein EL, et al, for the EIVI. Late safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent compared with a paclitaxel-eluting stent in patients with de novo coronary lesions: 2-Year follow-up from the ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions). J Am Coll Cardiol Intv 2009;2:1208–1218.

9. Stone GW, Midei M, Newman W, et al, for the SIIII. Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: Two-year clinical follow-up from the clinical evaluation of the Xience V everolimus-eluting coronary stent system in the treatment of patients with de novo native coronary artery lesions (SPIRIT) III trial. Circulation 2009;119:680–686.

10. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: Data from a large two-institutional cohort study. Lancet 2007;369:667–678.

11. Blich M, Zeidan-Shwiri T, Petcherski S, et al. Incidence, predictors and outcome of drug eluting stent thrombosis in real world practice. J Invasive Cardiol 2010;22:461–464.

12. Ellis SG, Bajzer CT, Bhatt DL, et al. Real-world bare metal stenting: Identification of patients at low or very low risk of 9-month coronary revascularization. Catheter Cardiovasc Interv 2004;63:135–140.

13. Austin D, Oldroyd KG, McConnachie A, et al. Drug-eluting stents versus bare-metal stents for off-label indications: A propensity score-matched outcome study. Circ Cardiovasc Intervent 2008;1:45–52.

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